(R)-(-)-2,2-DIMETHYL-1,3-DIOXOLAN-4-YLMETHYL P-TOLUENESULFONATE

(R)-(-)-2,2-DIMETHYL-1,3-DIOXOLAN-4-YLMETHYL P-TOLUENESULFONATE Property

Melting point:

41-43 °C(lit.)

Boiling point:

398.71°C (rough estimate)

Density 

1.208 g/mL at 25 °C(lit.)

refractive index 

n20/D 1.506(lit.)

Flash point:

>230 °F

storage temp. 

-20°C

solubility 

Dichloromethane; Chloroform; Ethyl Acetate; Methanol; DMF;

form 

Oil

color 

Pale Brown

optical activity

[α]/D 7.0±0.5°, neat

BRN 

89800

InChI

InChI=1/C13H18O5S/c1-10-4-6-12(7-5-10)19(14,15)17-9-11-8-16-13(2,3)18-11/h4-7,11H,8-9H2,1-3H3/t11-/s3

InChIKey

SRKDUHUULIWXFT-LLVKDONJSA-N

SMILES

C1(C=CC(C)=CC=1)S(=O)(=O)OC[C@H]1COC(C)(C)O1 |&1:12,r|

CAS DataBase Reference

23788-74-1(CAS DataBase Reference)

Safety

Hazard Codes 

Xi,Xn

Risk Statements 

36/37/38-22

Safety Statements 

26-36-37/39

WGK Germany 

3

F 

10-21

HS Code 

29329900

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

Precautionary statements

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

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

(R)-(-)-2,2-DIMETHYL-1,3-DIOXOLAN-4-YLMETHYL P-TOLUENESULFONATE Chemical Properties,Usage,Production

Chemical Properties

clear yellow to light brown viscous liquid

Uses

(R)-(-)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl p-Toluenesulfonate is a chiral building block. It is used to prepare the antifungal agent ketoconazole. It is also used to prepare acyclic Nucleotide Analogs Derived from 8-Azapurines with antiviral activities.

Synthesis

To a solution of (S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane (19a) (4.0 g, 30.2 mmol) in anhydrous pyridine (50 mL) was added p-toluenesulfonyl chloride (6.18 g, 31.7 mmol) in batches over a period of 10 min under ice bath conditions. The reaction mixture was slowly brought to room temperature and stirred overnight, during which a white precipitate was observed to form. Upon completion of the reaction, the pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 mL) and washed sequentially with cold aqueous 1M HCl solution (2 x 150 mL), saturated NaHCO3 solution (100 mL) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a light yellow oil. The crude product was purified by silica gel column chromatography using a 10-30% ethyl acetate/hexane gradient elution to afford (R)-(-)-3-toluenesulfonyloxy-1,2-propanediol acetone compound (20a) (8.54 g, 99% yield, 99.9% ee) as a colorless viscous oily substance. rf = 0.37 (20% ethyl acetate/hexanes). [α]D20 -4.8 (c 1.0, EtOH) (literature value [α]D24 -4.6 (c 13.0, EtOH)). ftir (film) νmax 3073, 2987, 2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1177, 1096, 1055 , 979, 829, 788, 665, 555 cm-1.1H NMR (600MHz, CDCl3) δ1.31(s, 3H, CH3-2), 1.34(s, 3H, CH3-2), 2.45(s, 3H, ArCH3), 3.76(dd, J=5.1 and 8.8Hz, 1H, CH2-5), 3.98 (dd, J=6.0 and 10.2 Hz, 1H, CH2-1'), 3.99-4.05 (m, 2H, CH2-1' and CH2-5), 4.28 (m, 1H, CH-4), 7.35 (m, 2H, aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6) ppm.13C NMR ( 150MHz, CDCl3) δ21.5(Ar-CH3), 25.1(CH3-2), 26.5(CH3-2), 66.1(C-5), 69.4(C-1'), 72.8(C-4), 109.9(C-2), 127.9(2C, aromatic C-2 and C-6), 129.8(2C, aromatic C-3 and C-5), 132.6(m, 2H, aromatic C-3 and C-6) ppm. HRMS (ESI): C13H18NaO5S [M+Na]+ Calculated value 309.07672; Measured value 309.0762 Chiral HPLC analysis: Chiralpak IA column (5 μm, 250×4.6 mm), mobile phase hexane/2-propanol/methanol (2C, aromatic C-2 and C-6), 129.8 (2C, aromatic C-3 and C-5), 132.6 (aromatic C-1), 145.0 (aromatic C-4) ppm. Chiralpak IA column (5 μm, 250×4.6 mm), mobile phase hexane/2-propanol/methanol (97:2:1, v/v/v), flow rate 1.0 mL/min, tR=21.71 min (0.06% 20b), tR=24.20 min (99.94% 20a), 99.88% ee. All physical and spectroscopic data are in good agreement with those reported in the literature.

References

[1] Tetrahedron, 2013, vol. 69, # 5, p. 1634 - 1648
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3198 - 3213
[3] Patent: WO2013/133730, 2013, A1. Location in patent: Page/Page column 33; 34
[4] Patent: US2015/31898, 2015, A1. Location in patent: Paragraph 0221; 0222
[5] Pharmazie, 1998, vol. 53, # 6, p. 377 - 380