5-Chlorothiophene-2-sulfonyl chloride Chemical Properties

Melting point:

25-28°C

Boiling point:

112-117 °C (lit.)

Density 

1.623 g/mL at 25 °C (lit.)

refractive index 

n20/D 1.586(lit.)

Flash point:

>230 °F

storage temp. 

2-8°C

form 

solid

Specific Gravity

1.623

color 

Colorless to Yellow to Orange

Water Solubility 

Not miscible in water.

Sensitive 

Moisture Sensitive

BRN 

130710

InChI

InChI=1S/C4H2Cl2O2S2/c5-3-1-2-4(9-3)10(6,7)8/h1-2H

InChIKey

SORSTNOXGOXWAO-UHFFFAOYSA-N

SMILES

C1(S(Cl)(=O)=O)SC(Cl)=CC=1

CAS DataBase Reference

2766-74-7(CAS DataBase Reference)

Safety Information

Hazard Codes 

C

Risk Statements 

34-29-14

Safety Statements 

26-27-36/37/39-45-28A-25

RIDADR 

UN 3265 8/PG 2

WGK Germany 

3

Hazard Note 

Corrosive

HazardClass 

8

PackingGroup 

II

HS Code 

29349990

MSDS

• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS
• Language:English Provider:ALFA

5-Chlorothiophene-2-sulfonyl chloride Usage And Synthesis

Chemical Properties

5-Chlorothiophene-2-sulfonyl chloride is white to yellow crystalline low melting solid

Uses

5-Chloro-2-thiophenesulfonyl Chloride is a sulfonylthiophene derivative used in the preparation of Notch-1-sparing γ-secretase inhibitors for the treatment of Alzheimer's disease.

Uses

5-Chlorothiophene-2-sulfonyl chloride is an important raw material and intermediate used in Organic Synthesis, Pharmaceuticals, Agrochemicals and Dyestuffs. It is used in the preparation of Notch-1-sparing γ-secretase inhibitors for the treatment of Alzheimer's disease.

Synthesis Reference(s)

Tetrahedron, 21, p. 1333, 1965 DOI: 10.1016/S0040-4020(01)98293-6

General Description

5-Chlorothiophene-2-sulfonyl chloride can be prepared from 2-chlorothiophene by reacting with chlorosulfonic acid in the presence of phosphorus pentachloride.

Synthesis

The following procedure is adapted from C. A. Hunt et al. J. Med. Chem. 1994, 37, 240-247. chlorosulfonic acid (240 mL, 3.594 mol) was added to a three-necked round-bottomed flask equipped with a mechanical stirrer, air condenser, dropping funnel, and moisture-proof tubing. Phosphorus pentachloride (PCl5, 300 g, 1.44 mol, 0.40 eq.) was added in batches with stirring, taking 45 minutes. During the addition process, a large amount of hydrogen chloride gas was violently released, but the temperature of the mixture did not rise significantly (<40 °C). When all the PCl5 was added, an almost clear light yellow solution was formed with only a few solid fragments suspended in it. Stirring was continued until gas escape ceased (~0.5 h). Subsequently, the reaction vessel was cooled in an ice bath and 2-chlorothiophene (66.0 mL, 0.715 mol) was slowly added through a dropping funnel over a period of 1.0 hour. After the addition of the first few drops of 2-chlorothiophene, the mixture changed to a dark purple color, and when all the thiophene was added, a dark purple solution was formed. Hydrogen chloride gas was continuously released at a slow rate during the addition. The reaction mixture was stirred at room temperature overnight. Subsequently, the dark purple clear solution was added dropwise to crushed ice (3 L) over a period of 0.5 hours. The purple color disappeared instantly, except for the ice, and a colorless dilute emulsion was formed, which was mechanically stirred at room temperature for about 1 hour. Next, the mixture was extracted with dichloromethane (CH2Cl2, 3 x 300 mL). The combined dichloromethane extracts were washed sequentially with water (1 × 200 mL), saturated sodium bicarbonate solution (NaHCO3, 1 × 250 mL), and brine (1 × 100 mL), dried over anhydrous sodium sulfate (Na2SO4), and concentrated on a rotary evaporator to give the crude product as a pale white to pale yellow viscous mass, which gradually solidified into a semi-solid. Finally, it was purified by high vacuum distillation (boiling point 110-112 °C, pressure 712 mmHg) to obtain 135.20 g (88% yield) of 5-chlorothiophene-2-sulfonyl chloride as a colorless to light yellow semi-solid.

References

[1] Patent: WO2007/56167, 2007, A2. Location in patent: Page/Page column 33-34
[2] Patent: WO2008/137809, 2008, A2. Location in patent: Page/Page column 61-62
[3] Pharmazie, 1994, vol. 49, # 2-3, p. 115 - 117
[4] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 3, p. 1063 - 1064
[5] Justus Liebigs Annalen der Chemie, 1937, vol. 532, p. 250,279

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