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Synthesis of tert-butyl (R)-4-((2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxypiperidine-1-carboxylate

IP.com Disclosure Number: IPCOM000250238D
Publication Date: 2017-Jun-15
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Synthesis of tert-butyl (R)-4-((2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3-

yl)phenoxy)methyl)-4-hydroxypiperidine-1-carboxylate

This document provides a description of a manufacturing procedure for compound 1

1

according to Scheme 1:

Scheme 1

Stage-1 Preparation of 1-(benzyloxy)-2-fluoro-4-nitrobenzene, (3)

Water, KOH, tetra-n-butylammonium bromide (TBAB) and dichloromethane (DCM) are

charged followed by benzyl alcohol to the reaction mixture at 25-30 °C and stirred for 30 min.

3,4-difluoronitrobenzene 2 is added to the reaction mixture at 25-30° and maintained for 6 h

at 25-30 °C. After completion of the reaction, DCM is completely removed under reduced

pressure and the obtained solid is filtered and collected as 1-(benzyloxy)-2-fluoro-4-

nitrobenzene, 3 after drying. Yield: 98.00 %.

The reagents used and their quantities are summarized as follows:

No Reagents Density Molecular

weight Quantity Moles

Mole ratio

1 3,4-difluoro nitrobenzene 1.441 159 25 g 0.157 1

2 KOH 2.044 56.10 30.87 g 0.55 3.5

3 TBAB ---- 322.37 2.53 g 0.0078 0.05

4 Water 1.0 18 370 mL ---- 14.8 vol

5 Dichloromethane 1.32 84 165 mL ---- 6.6 vol

6 Benzyl alcohol 1.045 108.13 16.26 mL 0.06 1.0

Compound 3 is characterized by 1H-NMR and Mass spectrometry as follows:

No. Chemical shift Multiplicity Assignment

1 5.2 s (2H) Ar-CH2-O-

2 7.07 m (1H) Ar-H

3 7.4 m (5H) Ar-CH2-O-

4 8.0 m (2H) Ar-H

m/z (ESI), 247.21 (M+H)+.

Stage-2 Preparation of ethyl[4-(benzyloxy)-3-fluorophenyl]carbamate, (5)

Toluene, 3, water, iron powder and ammonium formate are charged and the reaction mass

heated to 50-55°C for 4 h. After completion of the reaction the mass is cooled to 20-25 °C

and filtered through a celite bed. The filter bed is washed with ethyl acetate and to the filtrate

NaHCO3 is added at 25-30°C. The reaction mass containing intermediate 4 is cooled to 0-

5°C and ethyl chloroformate is added. The reaction mixture is maintained for 4 h at 25-30°C

and the layers are separated. The organic layer is distilled under reduced pressure, and co-

distilled with n-heptane up to 2 vol. To the reaction mass n-heptane is added and stirred for

1 h at 0-5°C. The solid is filtered, washed with n-heptane and the obtained 5, ethyl[4-

(benzyloxy)-3-fluorophenyl]carbamate, is dried. Yield: 86%. Yield range: 70-97%.

The reagents used and their quantities are summarized as follows:

Compound 5 is characterized by 1H-NMR and Mass spectrometry as follows:

No. Chemical shift Multiplicity Assignment

1 1.30 t (3H) CH3 -CH2-O-

2 4.2 q (2H) CH3 -CH2-O-

3 5.1 s (2H) Ar-CH2-O-

4 6.9 t (2H) Ar-H

5 6.4 s NH-COO-

6 7.3 m (6H) Ar-H

m/z (ESI), 290.05 (M+H)+.

No Reagents Density Molecular

weight Quantity Moles Mole ratio

1 Compound 3 -- 247 100 g 0.404 1

2 Iron powder 7.86 55.8 90.44 g 1.619 4

3 Ammonium formate 1.28 63.06 108.50 g 1.72 4.25

4 Water 1.0 18 800 mL -- 8 vol

5 Toluene 0.866 92.14 800 mL -- 8 vol

6 Ethyl chloroformate 1.135 108.5 46.44 mL 0.48 1.2

7 NaHCO3 -- 84 119.02 g -- 3.5

8 Ethyl acetate 0.902 88.10 350...