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Supplementary Information
Highly enantioselective bioreduction of 1-(3,4-difluorophenyl)-3-nitropropan-1-one: Key intermediate of Ticagrelor
Manpreet Singh1, Hare Krishnen1, Goverdhan Gilla1, Kavitha Charugondla1, Karen Holt-Tiffin2 and Rakeshwar Bandichhor1*
*Corresponding author. Telephone: +91 40 44346430
Fax: +91 40 44346164
E-mail: [email protected]
Electronic Supplementary Material (ESI) for RSC Advances.This journal is © The Royal Society of Chemistry 2016
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Table of contents
Scheme 1 ................................................................................................................................................3
1. HPLC Methods ...............................................................................................................................4
a) Purity by HPLC: Standard ..........................................................................................................4
b) Purity by HPLC: 1-(3,4-difluorophenyl)-3-nitropropan-1-ol......................................................5
c) Chiral HPLC: Standards (1) (2) and (6)......................................................................................6
d) Chiral HPLC: Preparative batch sample .....................................................................................7
2. NMR spectra...................................................................................................................................8
a) 1H-NMR spectra: 1-(3,4-Difluorophenyl)-3-nitropropan-1-one .................................................8
b) 13H-NMR spectra: 1-(3,4-Difluorophenyl)-3-nitropropan-1-one ................................................9
c) 1H-NMR spectra: 1-(3,4-difluorophenyl)-3-nitropropan-1-ol...................................................10
3. Mass Spectrum: 1-(3,4-difluorophenyl)-3-nitropropan-1-ol.........................................................11
4. IR Spectrum: (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol .......................................................12
3
Scheme 1
FF
O
FF
NO2
FF
NH2Zn dust
(R)-(+)-2-Methyl-CBS-oxazaborolidine
F
F
HN
N
NNNNO
HO
HO OH
S CH3
NO2F
F
OH
NO2
PPh3
DEAD
chemocatalysis
biocatalysis
1 2
34
Ticagrelor, 5
C. parapsilosis, 85%, 98% ee
75%, 94% eereported F
F
OH
NO2
+
6
4
1. HPLC Methods
a) Purity by HPLC: Standard
Determined by HPLC using Zorbex Eclipse Plus C-18 at 210 nm. Mobile phase consisted of
A: 0.02 M KH2PO4 buffer pH 3.0 and B: ACN:H2O (90:10 v/v).
Figure S1: HPLC spectrum of standard substrate (1) and product (2).
1- RT 8.222- RT 7.71
5
b) Purity by HPLC: 1-(3,4-difluorophenyl)-3-nitropropan-1-ol
Determined by HPLC using Zorbex Eclipse Plus C-18 at 210 nm. Mobile phase consisted of
A: 0.02 M KH2PO4 buffer pH 3.0 and B: ACN:H2O (90:10 v/v).
Figure S2: HPLC spectrum of preparative scale batch 1-(3,4-difluorophenyl)-3-nitropropan-1-ol (2).
2-RT 7.53
6
c) Chiral HPLC: Standards (1) (2) and (6)
Determined by using chiral HPLC column Chiralcel OD-H at 210 nm. Mobile phase
consisted of Hexane/iPrOH/TFA (92:7.9:0.1).
Figure S3: Chiral HPLC spectrum of standard (1) (2) and (6).
1-RT 27.62-RT 15.156-RT 13.58
7
d) Chiral HPLC: Preparative batch sample
Determined by using chiral HPLC column Chiralcel OD-H at 210 nm. Mobile phase
consisted of Hexane/iPrOH/TFA (92:7.9:0.1).
Figure S4: Chiral HPLC spectrum of preparative batch showing (1), (2) and (6)
2
6
8
2. NMR spectra
a) 1H-NMR spectra: 1-(3,4-Difluorophenyl)-3-nitropropan-1-one
Figure S5: 1H NMR spectrum of 1-(3,4-difluorophenyl)-3-nitropropan-1-one in CDCl3.
FF NO2
O1
2
3 4
5
1, 2, 3
45
9
b) 13H-NMR spectra: 1-(3,4-Difluorophenyl)-3-nitropropan-1-one
Figure S6: 13C NMR spectrum of (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol in CDCl3.
FF NO2
O
1 2
34
569
78
1
2
3
4
5
6, 9
7, 8
10
c) 1H-NMR spectra: 1-(3,4-difluorophenyl)-3-nitropropan-1-ol
Figure S7: 1H NMR spectrum of (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol in CDCl3.
F
F
O2N
OH
12
3
4
5
6
7
1, 2, 3, 4
5, 6 7
11
3. Mass Spectrum: 1-(3,4-difluorophenyl)-3-nitropropan-1-ol
Figure S8: Mass (M-H) spectrum of (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol.
12
4. IR Spectrum: (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol
Figure S9: IR spectrum of (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol.