4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one Chemical Properties

Boiling point:

214℃

Density 

1.367

Flash point:

93℃

storage temp. 

Inert atmosphere,Store in freezer, under -20°C

solubility 

Chloroform (Slightly), Methanol (Slightly)

form 

liquid

pka

14.54±0.10(Predicted)

color 

Pale yellow

InChI

InChI=1S/C5H6O4/c1-3-4(2-6)9-5(7)8-3/h6H,2H2,1H3

InChIKey

JEQSUJXHFAXJOW-UHFFFAOYSA-N

SMILES

O1C(C)=C(CO)OC1=O

Safety Information

HS Code 

2932990090

4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one Usage And Synthesis

Description

4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one is a reagent used in organic synthesis, particularly for the introduction of the non-chiral (oxodioxolenyl)methyl carbamate group to active pharmaceutical ingredients (APIs) to afford the corresponding pro-drug.

Definition

4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one can be reacted with oxalyl chloride to afford (5-methyl-2-oxo-1,3-dioxol-4-yl) methylglyoxal chloride, which provides for an alternative approach to introduce the (oxodioxolenyl) methylcarbamate group.

Uses

4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one is used in preparation method of key intermediate of olmesartan medoxomil.

Preparation

At 20-25°C, 50 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one and 45 g of formic acid were added to 500 mL of acetonitrile. The reaction was cooled to 10-15°C followed by 95 g of triethylamine added. The mixture was heated to 60-65°C and stirred for approximately 5-6 h. The reaction system was subsequently cooled to 15-20°C, filtered, and washed with acetonitrile. Collecting filtrate, and the acetonitrile was removed under vacuum to concentrate the solution. The reaction system was again cooled to 25-30°C, and ethyl acetate and water were added. The mixture was then stirred for approximately 15-20 minutes at 25-30°C. Finally, 4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one was obtained after further purification.

Synthesis

Example 4 Preparation of 4-hydroxymethyl-5-methyl-1,3-dioxolan-2-one: 4-chloromethyl-5-methyl-1,3-dioxolan-2-one (50 g) was dissolved in acetonitrile (500 ml), and formic acid (45 g) was slowly added at 20-25 °C. The reaction mixture was then cooled to 10-15 °C and triethylamine (95 g) was added. The reaction system was heated to 60-65°C and the reaction was kept at this temperature with stirring for 5-6 hours. After completion of the reaction, the mixture was cooled to 15-20 °C, filtered and the filter cake was washed with acetonitrile. The filtrates were combined and the acetonitrile was removed by distillation under reduced pressure to concentrate the solution. The concentrated reaction was cooled to 25-30 °C, ethyl acetate and water were added and stirred at 25-30 °C for 15-20 minutes. The aqueous layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with brine. The organic layer was separated and evaporated to dryness at 35-40°C under reduced pressure. Methanol was added to the residual oil and heated to reflux temperature. Isopropanol solution of HCl was added dropwise and the reaction was refluxed for 60-75 minutes. At the end of the reaction, it was cooled to 30-35 °C and distilled under reduced pressure to remove all solvent to give 4-(hydroxymethyl)-5-methyl-[1,3]dioxolen-2-one as an oily product (yield: 34.6 g; yield: 79%).

References

[1] Patent: WO2012/107814, 2012, A1. Location in patent: Page/Page column 14-15
[2] Patent: CN105492423, 2016, A. Location in patent: Paragraph 0741; 0742; 0743; 0744
[3] Patent: TW2016/2093, 2016, A. Location in patent: Paragraph 0323
[4] Patent: US2016/194302, 2016, A1. Location in patent: Paragraph 0413; 0414

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