7716-66-7

Basic information

• Product Name: 3-Chloro-1,2-benzisothiazole
• Synonyms: 3-CHLORO-1,2-BENZISOTHIAZOLE;3-CHLORO-1,2-BENZOISOTHIAZOLE;3-CHLORO-BENZO[D]ISOTHIAZOLE;3-CHLOROBENZISOTHIAZOLE;CHLOROBENZO[D]ISOTHIAZOLE;3-Chloro-1,2-Benzisonthiazole;1,2-benzisothiazole,3-(1-piperazinyl)-,monohydrochloride;2H-indole-2-one,6-choro-5-(2-chloroethyl)-1,3-dihydro
• CAS NO: 7716-66-7
• Molecular Formula: C₇H₄ClNS
• Molecular Weight: 169.63
• EINECS: -0
• Product Categories: Intermediates of Dyes and Pigments;Sulphur Derivatives;Heterocyclic Compounds;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 7716-66-7.mol
• Article Data: 14

Chemical Properties

• Melting Point: 38-39°C
• Boiling Point: 80-86°C 0,75mm
• Flash Point: 80-86°C/0.75mm
• Appearance: white solid
• Density: 1.435 g/cm³
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• Solubility: Soluble in Chloroform, Dichloromethane and Ethyl Acetate.
• PKA: 1.05±0.50(Predicted)
• BRN: 119370
• CAS DataBase Reference: 3-Chloro-1,2-benzisothiazole(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Chloro-1,2-benzisothiazole(7716-66-7)
• EPA Substance Registry System: 3-Chloro-1,2-benzisothiazole(7716-66-7)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36/37/39-37
• Hazardous Substances Data: 7716-66-7(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

3-Chloro-1,2-benzisothiazole is used as an intermediate of Ziprasidone.

Synthetic route

1,2-benzisothiazolin-3-one (2634-33-5) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
In chlorobenzene; paraffin oil	92.7%
With thionyl chloride; N,N-dimethyl-formamide In chlorobenzene at 70 - 80℃; for 9h;	90%
With tetramethylurea In chlorobenzene	84.9%

2-(trimethylsilyl)phenyl trifluoromethanesulfonate (88284-48-4) + 3,4-dichloro-1,2,5-thiadiazole (5728-20-1) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
With cesium fluoride In tetrahydrofuran Reagent/catalyst; Solvent; Inert atmosphere;	76%

benzenedizolium-2-carboxylate (1608-42-0) + 3,4-dichloro-1,2,5-thiadiazole (5728-20-1) → 3-chloro-1,2-benzisothiazole (7716-66-7) + ClCN

Conditions	Yield
In tetrahydrofuran for 0.5h; Heating;	A 35% B n/a

1,2-benzisothiazol-3-one (2634-33-5) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
With triethylamine; trichlorophosphate

3-Chlor-2-methyl-1,2-benzisothiazoliumchlorid (4163-05-7) → 3-chloro-1,2-benzisothiazole (7716-66-7)

1.2-benzisothiazolone → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
With phosphorus pentachloride; trichlorophosphate at 130 - 140℃;

2,2'-dithiodibenzoic acid dichloride (19602-82-5) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: Cl2 / CH2Cl2 2: concd NH4OH / CH2Cl2 / 1 h 3: 77 percent / POCl3 / 3.5 h / 20 - 120 °C View Scheme

2,2'-dithiobenzoic acid (119-80-2) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 71 percent / SOCl2 / dimethylformamide; toluene / 18 h / 75 °C 2: Cl2 / CH2Cl2 3: concd NH4OH / CH2Cl2 / 1 h 4: 77 percent / POCl3 / 3.5 h / 20 - 120 °C View Scheme

2-chlorosulfenylbenzoyl chloride (3950-02-5) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: concd NH4OH / CH2Cl2 / 1 h 2: 77 percent / POCl3 / 3.5 h / 20 - 120 °C View Scheme

anthranilic acid (118-92-3) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: pentyl nitrile 2: 35 percent / tetrahydrofuran / 0.5 h / Heating View Scheme

1,2-benzisothiazolin-3-one (2634-33-5) + water (7732-18-5) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
With trichlorophosphate

3-methoxy-1,2-benzoisothiazole (40991-38-6) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
With tributyl-amine; trichlorophosphate at 20 - 115℃;	6.97 g

3-methoxy-4-chloro-1,2,5-thiadiazole (5728-16-5) + 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (88284-48-4) → 3-chloro-1,2-benzisothiazole (7716-66-7) + 3-methoxy-1,2-benzoisothiazole (40991-38-6)

Conditions	Yield
With cesium fluoride In tetrahydrofuran at 60℃; Inert atmosphere; Overall yield = 75 %;

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (88284-48-4) → 3-chloro-1,2-benzisothiazole (7716-66-7) + 3-(morpholin-4-yl)-1,2-benzoisothiazole (22801-59-8)

Conditions	Yield
With cesium fluoride In tetrahydrofuran at 60℃; Inert atmosphere; Overall yield = 83 %;

2-Chlorobenzonitrile (873-32-5) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; sodium hydroxide; Octanethiol / chlorobenzene; water / 4 h / 65 - 70 °C / Inert atmosphere 2: thionyl chloride / chlorobenzene; N,N-dimethyl-formamide / 10 h / 75 °C View Scheme

2-cyanothioanisole (6609-54-7) → 3-chloro-1,2-benzisothiazole (7716-66-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; chlorine / chlorobenzene; water / 1.5 h / 25 - 65 °C 2: trichlorophosphate / N,N-dimethyl-formamide; toluene / 3.5 h / 0 - 60 °C / Inert atmosphere View Scheme

3-chloro-1,2-benzisothiazole (7716-66-7) + 4-[4-(4-chloro-phenyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-piperidine (859154-07-7) → 3-{4-[4-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}-1,2-benzisothiazole

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 48h;	98%

piperazine (110-85-0) + 3-chloro-1,2-benzisothiazole (7716-66-7) → 1-(2-cyanophenylthio)piperazine

Conditions	Yield
In tetrahydrofuran at 60 - 65℃; for 17h; Inert atmosphere;	89%

3-chloro-1,2-benzisothiazole (7716-66-7) + Methyl phenyldiazoacetate (22979-35-7) → methyl 4-chloro-2-phenyl-2H-benzo[e][1,3]thiazine-2-carboxylate (1044822-25-4)

Conditions	Yield
dirhodium tetraacetate In dichloromethane for 0.25h; Heating;	88%

3-chloro-1,2-benzisothiazole (7716-66-7) + malonic acid dimethyl ester (108-59-8) → 3-Amino-benzo[b]thiophene-2-carboxylic acid methyl ester (35212-85-2)

Conditions	Yield
Stage #1: malonic acid dimethyl ester With sodium methylate In methanol for 0.0833333h; Inert atmosphere; Stage #2: 3-chloro-1,2-benzisothiazole In methanol at 20℃; for 0.5h; Reagent/catalyst; Inert atmosphere;	88%

3-chloro-1,2-benzisothiazole (7716-66-7) + o-trifluoromethylphenyl bromide (392-83-6) → 3-(2-trifluoromethylphenyl)benzisothiazole (1393880-01-7)

Conditions

Yield

Stage #1: o-trifluoromethylphenyl bromide With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: 3-chloro-1,2-benzisothiazole With potassium phosphate; chloro-(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) In tetrahydrofuran; hexane; water at 40℃; for 2h; Suzuki-Miyaura Coupling; Inert atmosphere;

87%

piperazine (110-85-0) + 3-chloro-1,2-benzisothiazole (7716-66-7) → 3-(1-piperazinyl)-1,2-benzisothiazole (87691-87-0)

Conditions	Yield
In ethanol at 80℃; for 36h;	85%
In ethanol at 80℃; for 18h;	79.6%
at 125℃; for 24h;	68%

3-chloro-1,2-benzisothiazole (7716-66-7) + 1-phenoxy-2-propanol (770-35-4) → 3-((1-phenoxypropan-2-yl)oxy)benzo[d]isothiazole

Conditions	Yield
With C52H70NO5PPdS; sodium t-butanolate In tetrahydrofuran at 20℃; for 18h; Sealed tube; Schlenk technique;	81%

3-chloro-1,2-benzisothiazole (7716-66-7) + phenylacetonitrile (140-29-4) → 2-fenil-2-(1,2-benzisotiazol-3-il)acetonitrile (86004-79-7)

Conditions	Yield
With sodium ethanolate In ethanol for 2h; Heating;	80%
With sodium ethanolate

piperazine (110-85-0) + 3-chloro-1,2-benzisothiazole (7716-66-7) → 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride (87691-88-1)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol; toluene; tert-butyl alcohol	80%
With hydrogenchloride In water; toluene; tert-butyl alcohol	80%
With hydrogenchloride In water; isopropyl alcohol; toluene; tert-butyl alcohol	80%

3-chloro-1,2-benzisothiazole (7716-66-7) + acetylacetone (123-54-6) → 2-acetyl-3-aminobenzothiophen (34263-61-1)

Conditions	Yield
Stage #1: acetylacetone With sodium ethanolate In ethanol for 0.333333h; Stage #2: 3-chloro-1,2-benzisothiazole In ethanol at 20℃; for 16h;	80%

3-chloro-1,2-benzisothiazole (7716-66-7) + 2-propylzinc bromide lithium chloride → 3-isopropyl-benzo[d]isothiazole

Conditions	Yield
With 2′-(dicyclohexylphophanyl)-N2,N2,N6,N6-tetramethyl[1,1′-biphenyl]-2,6-diamine; C13H13NO3PdS In tetrahydrofuran; toluene at 0 - 20℃; for 1h; Negishi Coupling; Inert atmosphere;	78%

3-chloro-1,2-benzisothiazole (7716-66-7) + diethyl malonate (105-53-3) → ethyl 3-aminobenzothiophene-2-carboxylate (34761-09-6)

Conditions	Yield
Stage #1: diethyl malonate With sodium ethanolate In ethanol for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: 3-chloro-1,2-benzisothiazole In ethanol for 24h; Inert atmosphere;	76%
Stage #1: diethyl malonate With sodium ethanolate In ethanol for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: 3-chloro-1,2-benzisothiazole In ethanol for 24h; Inert atmosphere;	76%
Stage #1: diethyl malonate With sodium ethanolate In ethanol for 0.333333h; Cooling with ice; Inert atmosphere; Stage #2: 3-chloro-1,2-benzisothiazole In ethanol for 24h; Inert atmosphere;	76%

piperidine (110-89-4) + 3-chloro-1,2-benzisothiazole (7716-66-7) → 3-(piperidin-1-yl)-1,2-benzoisothiazole (22801-60-1)

Conditions	Yield
Reflux;	70.8%

3-chloro-1,2-benzisothiazole (7716-66-7) + p-chlorobenzyl cyanide (140-53-4) → 2-(4-clorofenil)-2-(1,2-benzisotiazol-3-il)acetonitrile (87792-16-3)

Conditions	Yield
With sodium ethanolate In ethanol for 2h; Heating;	70%

piperazine (110-85-0) + 3-chloro-1,2-benzisothiazole (7716-66-7) → 3,3'-(1,4-piperazinyl)-1,2-benzisothiazole + 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride (87691-88-1)

Conditions	Yield
With pyridine at 115 - 119℃; for 25h; Temperature; Solvent; Inert atmosphere;	A n/a B 67%

3-chloro-1,2-benzisothiazole (7716-66-7) + 3,4-dichloro-benzeneacetonitrile (3218-49-3) → 2-(3,4-diclorofenil)-2-(1,2-benzisotiazol-3-il)acetonitrile (87792-17-4)

Conditions	Yield
With sodium ethanolate In ethanol for 2h; Heating;	65%

3-chloro-1,2-benzisothiazole (7716-66-7) + 3,4-dihydro-7-methoxybenzofuro[2,3-c]pyridine-2(1H)-butanamine (263544-12-3) + butan-1-ol (71-36-3) → N-(1,2-benzisothiazol-3-yl)-3,4-dihydro-7-methoxybenzofuro[2,3-c]pyridine-2(1H)-butanamine monohydrochloride monohydrate

Conditions	Yield
With sodium hydrogencarbonate In dichloromethane; acetone	61%

3-chloro-1,2-benzisothiazole (7716-66-7) + 3,4-dimethoxyphenylacetonitrile (93-17-4) → Benzo[d]isothiazol-3-yl-(3,4-dimethoxy-phenyl)-acetonitrile

Conditions	Yield
With sodium ethanolate In ethanol for 2h; Heating;	60%

3-chloro-1,2-benzisothiazole (7716-66-7) + C12H15BrO2Zn → 4-(benzo[d]isothiazol-3-yl)pentyl benzoate

Conditions	Yield
With [1,3-bis(2,6-diisoheptylphenyl)-4,5-dichloroimidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride In tetrahydrofuran; toluene at 0 - 23℃; Negishi Coupling; Inert atmosphere; Schlenk technique;	59%

3-chloro-1,2-benzisothiazole (7716-66-7) → 3-aminobenzisothiazole (23031-78-9)

Conditions	Yield
With ammonia In formamide at 130℃; for 0.75h;	58%

3-chloro-1,2-benzisothiazole (7716-66-7) + malonic acid dimethyl ester (108-59-8) → dimethyl 2,1-benzoisothiazole-3-malonate

Conditions	Yield
With sodium acetate In tetrahydrofuran; ethanol at 20℃; for 24.5h; Inert atmosphere; Reflux;	57%

3-chloro-1,2-benzisothiazole (7716-66-7) + p-methoxybenzylnitrile (104-47-2) → Benzo[d]isothiazol-3-yl-(4-methoxy-phenyl)-acetonitrile

Conditions	Yield
With sodium ethanolate In ethanol for 2h; Heating;	45%

3-chloro-1,2-benzisothiazole (7716-66-7) → [3,3']bi[benzo[d]isothiazolyl]

Conditions	Yield
With piperazine at 120℃; for 24h;	30.8%

3-chloro-1,2-benzisothiazole (7716-66-7) → 3,5-dibromo-1,2-benzisothiazole + 3,7-dibromo-1,2-benzisothiazole (155167-97-8)

Conditions	Yield
With bromine; iron(III) chloride In acetic acid for 20h; Heating;	A n/a B 18%

3-chloro-1,2-benzisothiazole (7716-66-7) → 3-chloro-7-nitro-1,2-benzisothiazole (41533-75-9)

Conditions	Yield
With sulfuric acid; potassium nitrate at 0℃; for 3h;	15%
With sulfuric acid; potassium nitrate at 0 - 26℃; for 12h;	220 mg

3-chloro-1,2-benzisothiazole (7716-66-7) + 8-<4-(3-methyl-1-piperazinyl)butyl>-8-azaspiro<4.5>decane-7,9-dione (80827-65-2) → 8-<4-<4-(1,2-benzisothiazol-3-yl)-3-methyl-1-piperazinyl>butyl>-8-azaspiro<4.5>decane-7,9-dione (99748-55-7)

Conditions	Yield
at 120℃; for 16h;	8%

Upstream product

• 4163-05-7 3-Chlor-2-methyl-1,2-benzisothiazoliumchlorid 
• 1608-42-0 benzenedizolium-2-carboxylate 
• 5728-20-1 3,4-dichloro-1,2,5-thiadiazole 
• 6609-54-7 2-cyanothioanisole 
• 873-32-5 2-Chlorobenzonitrile 
• 30165-96-9 3-Morpholino-4-chloro-1,2,5-thiadiazole 
• 88284-48-4 2-(trimethylsilyl)phenyl trifluoromethanesulfonate 
• 5728-16-5 3-methoxy-4-chloro-1,2,5-thiadiazole 
• 40991-38-6 3-methoxy-1,2-benzoisothiazole 
• 2634-33-5 1,2-benzisothiazolin-3-one 
• 7732-18-5 water 
• 118-92-3 anthranilic acid 
• 119-80-2 2,2'-dithiobenzoic acid 
• 19602-82-5 2,2'-dithiodibenzoic acid dichloride 

Downstream Products

• 19767-25-0 3-(2-piperidin-1-yl-ethoxy)-benzo[d]isothiazole 
• 87691-87-0 3-(1-piperazinyl)-1,2-benzisothiazole 
• 86004-79-7 2-fenil-2-(1,2-benzisotiazol-3-il)acetonitrile 
• 87792-17-4 2-(3,4-diclorofenil)-2-(1,2-benzisotiazol-3-il)acetonitrile 
• 87792-16-3 2-(4-clorofenil)-2-(1,2-benzisotiazol-3-il)acetonitrile 
• 23031-78-9 3-aminobenzisothiazole 
• 87691-88-1 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride 
• 41533-75-9 3-chloro-7-nitro-1,2-benzisothiazole 
• 1259399-34-2 C₂₁H₂₅N₃O₂S 
• 1393880-01-7 3-(2-trifluoromethylphenyl)benzisothiazole 
• 34761-09-6 ethyl 3-aminobenzothiophene-2-carboxylate 
• 36822-08-9 <1>benzothieno<3,2-d>pyrimidin-4(3H)-one 
• 36822-09-0 4-chloro-3,4-dihydrobenzo[4,5]thiophene[3,2-d]pyrimidine 
• 35212-85-2 3-Amino-benzo[b]thiophene-2-carboxylic acid methyl ester 

Relevant articles and documents

Unexpected ring-expansion of 1,2-benzisoxazol-3-ones

A novel and unexpected ring-expansion reaction of 1,2-benzisoxazol-3-ones is identified. The scope of this reaction is exemplified and the proposed mechanism is also implicated in another degradation process. This reaction also represents a new method for accessing the 4H-1,3-benzoxazin-4-one skeleton.

Dimer impurity in ziprasidone hydrochloride raw material and preparation method thereof

The invention provides a dimer impurity in a ziprasidone hydrochloride raw material. The dimer impurity has a structure as shown in a formula 1. According to the invention, research and experiment are carried out from the mechanism direction, and it is believed that the compound 3-chloro-1, 2-benzothiazole can be subjected to self-condensation in the reaction process to generate the dimer impurity with the structure as shown in the formula 1. The impurity has extremely poor solubility and is slightly soluble in dimethyl sulfoxide or dichloromethane. The 3-chloro-1, 2-benzothiazole dimer impurity can be remained in the API without being controlled and removed, so the control of the dimer impurity in the preparation process of the 3-chloro-1, 2-benzothiazole and the anhydrous piperazine is particularly important. The invention further provides a preparation method for obtaining the high-purity ziprasidone hydrochloride dimer impurity, and the method is simple, high in controllability and mild in condition. The ziprasidone hydrochloride pharmaceutical composition can be used for ziprasidone hydrochloride process research and development, production, quality standard establishment and quality control links, and provides technical support for ziprasidone hydrochloride medication safety.

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