An Improved Process for Synthesis of (S)-Duloxetine Hydrochloride Involving Enzymatic Asymmetric Carbonyl Reduction on a Novel Ketoamine

Full text of DOI:10.1080/00304948.2020.1818527

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
An Improved Process for Synthesis of (S)-
Duloxetine Hydrochloride Involving Enzymatic
Asymmetric Carbonyl Reduction on a Novel
Ketoamine
Sachin A. Sasane , Mofazzal Husain , Nandu B. Bhise , Girij P. Singh , Alex
Joseph & Gautham G. Shenoy
To cite this article: Sachin A. Sasane , Mofazzal Husain , Nandu B. Bhise , Girij P. Singh , Alex
Joseph & Gautham G. Shenoy (2020): An Improved Process for Synthesis of (S)-Duloxetine
Hydrochloride Involving Enzymatic Asymmetric Carbonyl Reduction on a Novel Ketoamine, Organic
Preparations and Procedures International, DOI: 10.1080/00304948.2020.1818527
To link to this article: https://doi.org/10.1080/00304948.2020.1818527
Published online: 27 Oct 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1818527
EXPERIMENTAL PAPER
An Improved Process for Synthesis of (S)-Duloxetine
Hydrochloride Involving Enzymatic Asymmetric Carbonyl
Reduction on a Novel Ketoamine
a
a
a
a
b
Sachin A. Sasane , Mofazzal Husain , Nandu B. Bhise , Girij P. Singh , Alex Joseph ,
b
and Gautham G. Shenoy
a
b
Chemical Research and Development, Lupin Ltd., Mulshi, Pune, Maharashtra, India; Manipal Academy
of Higher Education, Manipal, Karnataka, India
ARTICLE HISTORY Received 27 November 2019; Accepted 15 June 2020
(
S)-Duloxetine hydrochloride 1 is a medication used to treat major depressive disorder,
1
,2
generalized anxiety disorder, fibromyalgia and neuropathic pain (Figure 1). Due to its
versatility in different treatments, many researchers have been attracted towards the
development of different cost-effective synthetic routes. The drug contains a 3-aryloxy-
3
-aryl propylamine sub-unit in its basic structure. It acts as a dual inhibitor of serotonin
3
–5
and norepinephrine reuptake.
A literature search reveals that most of the reported methods involve synthesis of
6
–20
enantiomerically pure alcohols as key chiral synthons, as presented in Scheme 1.
In our research work, we have focused on the development of an efficient route for
the synthesis of (S)-duloxetine hydrochloride 1 by modification of ketoamine intermedi-
ate a (Scheme 1), followed by enzymatic asymmetric reduction to obtain enantio-
merically pure alcohol intermediate b (Scheme 1). To help with our planning, we did
the retrosynthetic analysis shown in Scheme 2.
In our previous experience in the synthesis of 1, we observed that demethylation of 7
(
Scheme 2, when R ¼ CH ) to produce duloxetine free base 8 gives a low yield. This
3
was because of impurity formation during demethylation. Indeed, for the ease of deme-
thylation, many researchers had tried different substituents on the nitrogen of keto-
amine 5 in their synthetic routes.
1
7,21–24
We anticipated that the presence of a chiral
auxiliary on the nitrogen of ketoamine intermediate 5 could provide a suitable chiral
environment during enzymatic carbonyl reduction and could be more easily dealkylated.
Accordingly, we designed the synthetic route depicted in Scheme 3.
A Mannich reaction was carried out using 2-acetylthiophene, paraformaldehyde and
(
S)-N-methyl-1-phenylethan-1-amine hydrochloride in aqueous ethanol using conc.
hydrochloric acid to obtain ketoamine intermediate 9 (Scheme 3) in good yield. As we
know that enzymes are substrate specific and behave differently on different substrates,
even for the same reaction, it was necessary to carry out a screening study. Screening
experiments were done using 21 different commercially available ketoreductase enzymes
CONTACT Sachin A. Sasane
sachinsasane@lupin.com
Chemical Research and Development, Lupin Ltd., Mulshi,
Pune 412115, Maharashtra, India
ß 2020 Lupin Limited

2
S. A. SASANE ET AL.
Figure 1. (S)-Duloxetine hydrochloride.
Scheme 1. Literature routes for carbonyl reduction.
Scheme 2. Retrosynthetic analysis of (S)-dloxetine hydrochloride.
(
10 mg), substrate 9 (5 mg in 100 ml isopropanol) and 900 ml phosphate buffer having
ꢀ
pH 7.0 at a temperature 25-30 C. (Table 1)
Chiral HPLC analysis was carried out for the performed experiments, which showed
that enzyme CDX-008 (Table 1, Entry 13), does not have reactivity towards the sub-
strate. Enzyme KRED-P2-C02 (Entry 19) showed 98.8% conversion with 100% selectiv-
ity. Enzymes at Entries 5, 10, and 15 gave the unwanted R isomer in 11.1%, 11.4% and
19.0%, respectively. The rest of the enzymes showed 100% conversion with 100% select-
ivity. Based on the screening study experiments, we decided to work with CDX-021
(Entry 14) enzyme, as this is commercially available and has a low cost.
Bioreduction optimization conditions are important in the enantiomerically pure pro-
duction of chiral secondary alcohols since optimization of key conditions has been

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Scheme 3. Proposed reaction scheme for synthesis of (S)-Duloxetine hydrochloride.
shown to affect the enantiomeric excess (ee) of the product and conversion of the sub-
2
5
strate. To study the impact of pH on the reaction, phosphate buffers of different pH
were prepared and experiments were conducted (Table 2) which showed that reaction
at pH 6.0 had 15% conversion, but unidentified impurities formation was less. At pH
7.0, complete conversion was observed with formation of 5-10% unidentified impurities.
At pH 8.0, unidentified impurities formation was 50-60% and at pH 9.0 unidentified
impurities were observed at the level of 70-80%.
Further experiments were carried out to optimize the temperature using CDX-021
enzyme in phosphate buffer at pH 7.0, substrate 5 mg/100 ml isopropanol and 900 ml
buffer, nicotinamide adenine dinucleotide (NAD) 0.2%, enzyme 1% (Table 3).
ꢀ
ꢀ
An experiment conducted at 20 C showed around 75% conversion along with 5-10%
impurity formation, whereas at 40 C due to impurity formation only 40% of product
ꢀ
1
0 was obtained. At 30 C, reaction progress was satisfactory with 90% yield. Further, to
optimize enzyme load, two reactions were carried out using 10% and 1% CDX-021
enzyme with respect to substrate 9. Both the reactions showed the same conversion
using 30% isopropyl alcohol (IPA) and 70% phosphate buffer having pH 7.0 at tempera-
ꢀ
ture 28-30 C.
The reduction reaction was studied using different ratios of the phosphate buffer and
isopropanol with CDX-021 enzymes in phosphate buffer at pH 7.0, NAD 0.2%, enzyme
ꢀ
1
% (10 mg/ml), at temperature 28-30 C (Table 4).

4
S. A. SASANE ET AL.
Table 1. Screening of enzymes.
a
a
a
Entry
Enzyme code
Enzyme supplier
% Conversion
R-Isomer
S-Isomer
1
2
3
4
5
6
7
8
9
KRED-P1-B10
KRED-P1-B12
KRED-P1-C01
KRED-P1-H08
KRED-P2-B02
KRED-P2-D03
KRED-P2-D11
KRED-P2-D12
KRED-P2-H07
CDX-022
IEP_Ox58
IEP_Ox56
CDX-008
CDX-021
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Cambrex
Cambrex
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
Codexis
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
–
100%
100%
100%
100%
100%
98.8%
100%
100%
–
–
–
–
100%
100%
100%
100%
88.9%
100%
100%
100%
100%
88.6%
100%
100%
–
11.1%
–
–
–
–
1
1
1
1
1
1
1
1
1
1
2
2
a
0
1
2
3
4
5
6
7
8
9
0
1
11.4%
–
–
–
-
100%
81%
KRED-101
19.0%
KRED-NADH-110
KRED-P1-B02
KRED-P1-B05
KRED-P2-C02
KRED-P2-G03
KRED-P2-C11
–
–
–
–
–
–
100%
100%
100%
100%
100%
100%
Determined by HPLC.
Table 2. Study for impact of pH.
Entry
1
Enzyme
pH
6.0
Substrate loading
Buffer
% conversion
Observation
5 %
Impurity formation
5 - 10%
Impurity formation
50-60%
Impurity formation
70-80%
KRED-P1-B10
5 mg/ 100 ml
900 ml
10-15
100
100
2
3
4
KRED-P1-B10
KRED-P1-B10
KRED-P1-B10
7.0
8.0
9.0
5 mg/ 100 ml
5 mg/ 100 ml
5 mg/ 100 ml
900 ml
900 ml
900 ml
100
Impurity formation
Note: All observations are based on TLC estimates.
Table 3. Study of effect of temperature.
Entry
Enzyme
Temp
Time
% unreacted
% conversion
% impurity
Yield
ꢀ
1
2
3
CDX-021
CDX-021
CDX-021
20 C
21 Hr.
21 Hr.
21 Hr.
10 - 15%
75-80 %
100 %
100 %
5-10%
5 - 10%
50-60%
70%
90%
40%
ꢀ
30 C
0
0
ꢀ
40 C
Note: All observations are based on TLC estimates.
Experiments conducted using 10 to 30% IPA had given 100% conversion with less
impurity. With the increasing percentage of IPA, conversion went down with increasing
levels of impurities.
Based on our optimization experiment data, asymmetric reduction on ketoamine 9
was carried out on 10 g scale. Alcohol intermediate 10 was obtained with yield 98.5%
having enantiomeric excess 100%. Isolated alcohol intermediate 10 was condensed with
ꢀ
1
-fluoronaphthalene using potassium hydroxide in dimethyl sulfoxide at 75 C.
Intermediate 11 was obtained by solvent distillation followed by column chromatog-
raphy. Debenzylation of 11 was carried out using palladium on carbon under hydrogen
gas but was not successful. Hence, duloxetine base 8 was obtained by reaction of 11
with phenyl chloroformate and subsequent hydrolysis of the carbamate intermediate

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
Table 4. Study of buffer and solvent ratio.
Entry
Buffer
IPA
Time
% conversion
% impurity
Yield
1
2
3
4
90
70
50
10
10
30
50
90
21 Hr.
21 Hr.
21 Hr.
21 Hr.
100
100
70-80
10-15
5-10%
5-10%
15-20%
5-10%
90%
92%
55%
Not isolated
Note: All observations are based on TLC estimates.
with yield 70.3% We were pleased to see that this is an improvement over our observed
yield of 50% during the demethylation of 7, when R ¼ CH . Further conversion of
3
26
duloxetine base 8 to 1 was done according to the available literature.
In conclusion, we have synthesized a new ketoamine intermediate and devised experi-
mental conditions to obtain 100% ee for the carbonyl reduction during the synthesis of
(
S)-duloxetine hydrochloride using commercially available ketoreductase enzymes. Our
new method thus gives higher yield and excellent ee.
Experimental section
Reactions were conducted under an atmosphere of nitrogen wherever required.
Standard enzymes received from Codexis and Cambrex were used for experiments.
Reactions were monitored by TLC. TLCs were performed on silica gel using 30–50%
ethyl acetate in cyclohexane, visualized under UV short wavelength or using potassium
1
13
permanganate or p-anisaldehyde as staining reagents. H and C NMR spectra were
recorded using Bruker 400 and 500 MHz FT NMR spectrometers, and the chemical
shifts are reported in ppm d. Mass spectrometry was carried out using a Waters QDa
system. IR analysis was carried out using a Perkin-Elmer Spectrum 400 instrument.
Specific optical rotation analysis was carried out on an Autopol IV instrument. Chiral
HPLC was carried out using a Shimadzu LC-2010 system with UV detector and
Chiralpak IA-3 column at wavelength 207 nm.
(S)-3-(Methyl(1-phenylethyl)amino)-1-(thiophen-2-yl)propan-1-one (9)
A mixture of 2-acetylthiophene 2 (25.0 g, 0.198 mol), (S)-N-methyl-1-phenylethylamine
HCl 4 (37.5 g, 0.218 mol), paraformaldehyde 3 (8.2 g, 0.272 mol) and conc. HCl (25 mL)
ꢀ
in aqueous ethanol (25%, 250 mL) was heated at 75-85 C. Reaction progress was moni-
tored by TLC. After completion of the reaction in about 24 hr, ethanol was removed
from the reaction mass under vacuum and water (100 mL) was added. The reaction
mass was then extracted with diethyl ether (100 mL X 3) to wash out impurities. The
pH of the aqueous reaction mass was made basic (pH > 8.0) using sodium bicarbonate
solution and extracted using diethyl ether (200 mL X 2). The combined organic layer
having product was concentrated under vacuum to obtain an oily mass of crude ketone
intermediate 9 (35.0 g, 65%). To a clear solution of 9 (30.0 g, 0.105 mol) in isopropanol
(
5
150 mL) was added oxalic acid (14.0 g, 0.155 mol) and the mixture was heated to 50-
5 C for 10 min. The reaction mass was then cooled to room temperature. The solid
ꢀ
was filtered and further added to a mixture of water (200 mL) and diethyl ether
200 mL) and the pH of the mixture was made basic (pH > 8.0) using sodium bicar-
bonate solution. The organic layer was separated, dried over anhydrous sodium sulfate,
(

6
S. A. SASANE ET AL.
2
5
filtered and concentrated to obtain pure ketone intermediate 9 (24.5 gm, 82%); [a]
¼
D
ꢀ
ꢁ1
1
-
31.88 (c ¼ 1, methanol); IR (KBr): v
704, 1413, 1656 cm ; H-NMR (400 MHz,
max
CDCl ) d: 1.43-1.45 (d, J ¼ 7Hz, 3H), 2.32 (s, 3H,), 2.83-3.03 (m, 2H), 3.09-3.12
3
(
7
t, J ¼ 7.2 Hz, 2H), 3.65-3.70 (q, 1H), 7.14-7.16 (t, J ¼ 4 Hz, 1H), 7.27-7.35 (m, 5H),
1
3
.66-7.68 (m, 2H); C NMR (100 MHz, DMSO-d ): d ppm: 17.1, 34.3, 37.5, 48.8, 63.9,
6
1
28.1, 129.3, 129.5, 134.3, 134.6, 135.7, 143.6, 190.8; MS: (m/z) 274 (M þ 1).
Anal. Calcd for C H NOS: C, 70.29; H, 7.01; N, 5.12. Found C, 70.35; H, 7.08;
1
6
19
N, 5.25.
Phosphate Buffer Preparation (0.2 M, pH 7.00, 1 mM NAD, 2 mM MgSO4)
Monopotassium phosphate (KH PO ) (1.4 g) was dissolved in DM water (50 mL).
2
4
Similarly, dipotassium phosphate (K HPO ) (1.7 g) was dissolved in DM water (50 mL).
2
4
Both the solutions were mixed to adjust the pH to 7.00. To 50 mL of this solution was
added NAD (33.2 mg) and MgSO (24.6 mg).
4
(S)-3-(Methyl((S)-1-phenylethyl)amino)-1-(thiophen-2-yl)propan-1-ol (10)
Compound 9 (10.0 g) was dissolved in a mixture of isopropyl alcohol (30 mL) and buf-
fer solution (60 mL) (as above, i.e., 0.2 M potassium phosphate buffer, pH 7.00, 2 mM
MgSO ). To this mixture was added an enzyme solution (1.0 g enzyme and 0.1 mg NAD
4
ꢀ
dissolved in 10 mL buffer) and the mixture was stirred at 25-30 C for 20 hr. The reac-
tion was monitored by TLC. After completion of the reaction in about 21 hr, the isopro-
panol was distilled off from the reaction mixture and the remaining mass was extracted
using ethyl acetate (30 mL X 3). The combined organic layer was washed with 5% brine
solution and solvent was distilled off completely to obtain 10 (9.9 g, 99%); HPLC chiral
2
0
ꢀ
purity (ee) ¼ 100%; [a]
¼ -20.75 (c ¼ 0.35, methanol); IR (Neat): v
700, 1030,
max
D
ꢁ
1 1
3
2
338 cm ; H-NMR (500 MHz, CDCl ) d: 1.45-1.46 (d, J ¼ 7Hz, 3H), 1.97-2.00 (q, 2H),
3
.23 (s, 3H), 2.61-2.65 (m, 1H), 2.89-2.95 (m, 1H), 3.75-3.79 (q, 1H), 5.15-5.17
(
1
7
t, J ¼ 5Hz, 1H), 5.74 (D O exchangeable –OH, 1H), 6.92-6.93 (m, 1H), 6.97-6.99 (m,
2
1
3
H), 7.22-7.38 (m, 6H); C NMR (125 MHz, CDCl ): d ppm 16.7, 34.3, 37.5, 52.9, 63.8,
3
2.2, 122.2, 123.7, 126.6, 127.3, 127.9, 128.4, 141.5, 149.7; MS: (m/z) 276.05 (M þ 1).
Anal. Calcd for C H NOS: C, 69.78; H, 7.69; N, 5.09. Found C, 69.90; H, 7.48;
1
6
21
N, 5.20.
(S)-N-Methyl-3-(naphthalen-1-yloxy)-N-((S)-1-phenylethyl)-3-(thiophen-2-yl)propan-
1
-amine (11)
A mixture of compound 10 (8.0 g, 0.029 mol), 1-fluoronaphthalene (4.6 g, 0.032 mol)
and potassium hydroxide (14.4 g, 0.256 mol) in dimethyl sulfoxide (80 mL) was heated
ꢀ
at 70-75 C. Progress of reaction was monitored by TLC in ethyl acetate: cyclohexane
(3:7) mobile phase. After completion of reaction in about 22 hr, the mass was cooled to
room temperature and added to cold water (900 mL) with stirring. The reaction mixture
was extracted with cyclohexane (100 mL X 2). The combined organic layer was concen-
trated and purified by silica gel column chromatography (60-120 mesh) using 2-7%

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
7
ethyl acetate in hexane as the mobile phase to obtain intermediate 11 as an oil (8.5 g,
2
0
ꢀ
ꢁ1
1
7
3%); [a]D ¼ -29.67 (c ¼ 0.21, methanol); IR (Neat): v
699, 1095, 1264 cm ; H-
max
NMR (500 MHz, CDCl ) d: 1.31-1.33 (d, J ¼ 7Hz, 3H), 2.16-2.24 (m, 1H), 2.26 (s, 3H),
3
2
.34-2.47 (m, 1H), 2.51-2.56 (m, 1H), 2.63- 2.78 (m, 2H), 3.55-3.59 (q, 1H), 5.75-5.78
(
(
m, 1H), 6.85-7.00 (m, 3H), 7.11-7.31 (m, 7H), 7.40-7.42 (d, J ¼ 8Hz, 1H), 7.46-7.50
13
m, 2H), 7.78-7.80 (dd, J ¼ 1.5Hz, 8.5Hz, 1H), 8.23-8.25 (dd, J ¼ 1.5Hz, 8.5Hz, 1H);
C
NMR (125 MHz, CDCl ): d ppm; 18.1, 36.9, 38.4, 50.3, 63.4, 74.2, 106.78, 120.4, 122.2,
3
124.6, 125.1, 125.7, 126.2, 126.2, 126.5, 126.7, 127.4, 127.6, 128.0, 134.6, 145.7, 153.5;
MS: (m/z) 402.1 (M þ 1).
Anal. Calcd for C H NOS: C, 77.77; H, 6.78; N, 3.49. Found: C, 77.70; H, 6.58;
2
6
27
N, 3.51.
Acknowledgments
We thank Drs. Arun Natu and Rajeev Chikate (Garware College), Rajesh Vyas and Himanshu
Godbole (Lupin) for their guidance, support and suggestions. We are grateful to the analytical
support team of Lupin for sample analysis and to M/S Lupin Limited for support of the research
program and Ph.D. registration.
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