(R)-(-)-3-Pyrrolidinol hydrochloride

(R)-(-)-3-Pyrrolidinol hydrochloride Property

Melting point:

104-107 °C(lit.)

alpha 

-7.6°(20/D, c=3,5, CH3OH)

refractive index 

-7.8 ° (C=3.5, MeOH)

storage temp. 

Inert atmosphere,Room Temperature

solubility 

Soluble in DMSO.

form 

Solid

color 

Pale Brown

optical activity

[α]20/D 7.6°, c = 3.5 in methanol

BRN 

4450078

InChI

InChI=1/C4H9NO.ClH/c6-4-1-2-5-3-4;/h4-6H,1-3H2;1H/t4-;/s3

InChIKey

QPMSJEFZULFYTB-PGMHMLKASA-N

SMILES

[C@H]1(O)CNCC1.Cl |&1:0,r|

CAS DataBase Reference

104706-47-0(CAS DataBase Reference)

Safety

Hazard Codes 

Xi

Risk Statements 

36/37/38-41-38-37

Safety Statements 

26-36-38

WGK Germany 

3

F 

3-10

HS Code 

29339900

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P271Use only outdoors or in a well-ventilated area.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

(R)-(-)-3-Pyrrolidinol hydrochloride Chemical Properties,Usage,Production

Chemical Properties

Llight brown crystalline

Uses

(R)-3-Hydroxypyrrolidine hydrochloride is used as a darifenacin Intermediate.

Uses

(R)-3-Pyrrolidinol hydrochloride can be used as a building block to synthesize:

• Biaryl carboxamide functional groups containing bis-aminopyrrolidine ureas as potential antagonists of the melanin-concentrating hormone receptor-1.
• Pyrrolidinol based ionic liquids.
• Optically active 2-tritylpyrrolidine based organocatalysts.

Uses

(R)-(-)-3-Pyrrolidinol hydrochloride is a chiral hydroxy derivative of pyrrlodine used in the preparation of chiral niologically active compounds such as muscarinic receptor antagonists and antimicrobial agents.

Synthesis

Example 1: Preparation of (R)-3-hydroxypyrrolidine hydrochloride (Formula VII): cyclohexanol (80 liters) was added to the reactor and heated to 155°C. Water was removed by azeotropic distillation until the water content in the solvent did not exceed 0.2% (w/w). The solvent was then cooled to 45 °C and (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid (15 kg) was added and stirred for 10 min. Methyl isobutyl ketone (4.275 liters) was added to the reaction mixture, reheated to 154°C and maintained at this temperature for 5 hours of reaction. The reaction process was monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture was cooled to 0 °C under nitrogen protection and the pH was adjusted to 1.0-2.0 with ether-HCl (41 l). pH adjustment was completed, the temperature was raised to 25 °C and maintained for 2-3 h. The reaction mixture was then heated to 154 °C and maintained at this temperature for 5 h. The solid product was filtered and the reaction mixture was then heated to 154 °C. The solid product was collected by filtration and washed successively with ethyl acetate (30 liters in two portions) and isopropanol (15 liters). The wet solid was dried by suction for 1-2 hours and then dried under reduced pressure at 55°C for 5 hours to give 10.7 kg (R)-3-hydroxypyrrolidine hydrochloride in 76% yield and 98.5% HPLC purity.

Purification Methods

The (±)-isomer is purified by repeated distillation ( b 102-104o/12mm, 108-110o/18mm), and the (±)-picrate crystallises from EtOH with m 140-141o. The R(+)-enantiomer has b 70o/0.6mm and [] D +5.6o (c 3.63, MeOH). Its hydrochloride has a negative rotation and its dimethiodide has m 230o and [] 24 -8.02o. [Suyama & Kanno Yakugaku Zasshi (J Pharm Soc Japan) 85 531 1965, Uno et al. J Heterocycl Chem 24 1025 1987, Flanagan & Joullie Heterocycles 26 2247 1987, Beilstein 21 III/IV 44.]

References

[1] Patent: WO2008/100651, 2008, A2. Location in patent: Page/Page column 15; 32-33
[2] Patent: WO2015/110886, 2015, A1. Location in patent: Page/Page column 14
[3] Patent: WO2004/56767, 2004, A1. Location in patent: Page 14
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 10, p. 1764 - 1773