2-Oxa-7-azaspiro[3.5]nonane-7-carboxylic acid, 1,1-dimethylethyl ester

2-Oxa-7-azaspiro[3.5]nonane-7-carboxylic acid, 1,1-dimethylethyl ester Property

Melting point:

31-70°C

Boiling point:

315.8±42.0 °C(Predicted)

Density 

1.10

storage temp. 

-20°C

pka

-0.80±0.20(Predicted)

form 

solid

Appearance

White to off-white Solid

InChI

InChI=1S/C12H21NO3/c1-11(2,3)16-10(14)13-6-4-12(5-7-13)8-15-9-12/h4-9H2,1-3H3

InChIKey

YVHPBSHIEPPQDC-UHFFFAOYSA-N

SMILES

C1C2(CCN(C(OC(C)(C)C)=O)CC2)CO1

Safety

WGK Germany 

3

HS Code 

2934999090

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.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

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

P405Store locked up.

2-Oxa-7-azaspiro[3.5]nonane-7-carboxylic acid, 1,1-dimethylethyl ester Chemical Properties,Usage,Production

Uses

It is used as an active pharmaceutical intermediate.

Synthesis

The general procedure for the synthesis of tert-butyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate from tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate was as follows: to a solution of tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (60.0 g, 244.58 mmol) in anhydrous THF (1.2 L) was slowly added n-butyllithium ( nBuLi, 97.8 mL, 0.245 mol, 2.5 M) and the reaction mixture was stirred for 0.5 h at 0 °C. Subsequently, a solution of anhydrous THF (600 mL) of p-toluenesulfonyl chloride (TsCl, 46.6 g, 0.245 mmol) was added drop-wise, and the reaction process was monitored by thin-layer chromatography (TLC) until the feedstock was completely consumed, and stirring was continued for 1.5 hr at 0 °C. Again n-butyllithium (nBuLi, 97.8 mL, 0.245 mmol, 2.5 M) was added to the reaction mixture at 0 °C and stirred for 0.5 hours at 0 °C. Subsequently, the reaction mixture was warmed to 60 °C and stirred for 1 hour. Upon completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride (NH4Cl, 400 mL) solution at 0 °C. After separation of the organic layer, the aqueous layer was extracted with ethyl acetate (EtOAc, 300 mL x 3). The combined organic phases were washed with brine (800 mL × 2), dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure to give the crude product (65 g). The crude product was purified by fast column chromatography (eluent: petroleum ether (PE):ethyl acetate (EtOAc) = 30:1 to 10:1) to afford the target compound 2-oxa-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (37.0 g, 66% yield) as a white solid. The structure of the product was confirmed by 1H NMR (CDCl3) and mass spectrometry (MS): 1H NMR (CDCl3): δ1.47 (s, 9H), 1.83 (t, 4H, J=5.6Hz), 3.35 (t, 4H, J=5.6Hz), 4.46 (s, 4H); MS: 127.9 [M-Boc+H]+.

References

[1] Tetrahedron Letters, 2011, vol. 52, # 26, p. 3266 - 3270
[2] Patent: CN104557871, 2017, B