An Efficient Synthesis of Milnacipran Hydrochloride via Reductive Amination of Aldehyde

Article abstract of DOI:10.1155/2017/5385843

An efficient synthesis of milnacipran hydrochloride has been accomplished. The important application of this paper is the reductive amination of aldehyde to primary amine with water soluble reagents. This method provides a high yield of primary amine as t

Full text of DOI:10.1155/2017/5385843

Hindawi
Journal of Chemistry
Volume 2017, Article ID 5385843, 6 pages
https://doi.org/10.1155/2017/5385843
Research Article
An Efficient Synthesis of Milnacipran Hydrochloride via
Reductive Amination of Aldehyde
Neha Reddy Desireddy,1 Arava Glory,2 Krishna Reddy Bhimireddy,1
Yadagiri Kurra,3 and Ram Reddy1
1Nify Labs Pvt. Ltd., Hyderabad 500016, India
2Sri Venkateswara University, Tirupathi 517502, India
3Texas A&M University, College Station, TX 77843, USA
Correspondence should be addressed to Ram Reddy; ram.2006r@gmail.com
Received 14 November 2016; Revised 31 January 2017; Accepted 27 February 2017; Published 20 March 2017
Academic Editor: Mohamed Afzal Pasha
Copyright © 2017 Neha Reddy Desireddy et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
An efficient synthesis of milnacipran hydrochloride has been accomplished. e important application of this paper is the reductive
amination of aldehyde to primary amine with water soluble reagents. is method provides a high yield of primary amine as the
major product, reduces the number of steps, and discourages by-products.
1. Introduction
Generally protecting groups have been employed when
preparing primary amines via metal hydride reductive ami-
nation to control the overalkylation [3–9]. Protecting groups
have an important role in organic synthesis [10–13]. On
the other hand, the incorporation of protecting group into
synthetic route increases the total number of steps, decreases
yield, and decreases atom economy [14]. Protecting groups
also add functional groups and structural complexity to a
molecule, which can have detrimental effects on orthog-
onality and reactivity. In metal hydride reductive amina-
tions, the use of protecting groups is crucial to prevent
overalkylation [15, 16] (Scheme 2). In this reaction alde-
hyde (I) reacts with ammonia to form an imine (II) that
is subsequently reduced with sodium cyanoborohydride
Milnacipran hydrochloride is an antidepressant inhibiting
the recapture of serotonin-noradrenaline recommended in
the treatment of depression. US Food and Drug Adminis-
tration (FDA) approved milnacipran under the brand name
of Savella5 for the treatment of fibromyalgia [1, 2]. Several
research groups [3–6] show high interest to devise an efficient
synthesis of milnacipran with high enantiomeric purity.
Because it is hydrophilic molecule with low lipophilicity
makes this molecule differ from other drugs. Due to fea-
tures, milnacipran exhibits almost ideal pharmacokinetics in
humans (see Scheme 1).
Interesting structural features combined with the impor-
tant biological activity of milnacipran have attracted us to
attempt its synthesis through the oxidation and reductive
amination method.
e primary amines are important building blocks in
pharmaceutical and agrochemical industries and also useful
applications in organic chemistry. e primary amine of
milnacipran acts as chromophore and based on hydrophilic
makes this molecule differ from other drugs. e synthesis
of primary amine is very challenging reaction to avoid the
overalkylation when employed metal reductive amination.
(NaCNBH ) [17] to give the desired amine product (III).
3
Without a protecting group, multiple alkylation events typ-
ically occur, resulting in the formation of the undesired
secondary (V) or tertiary (VI) amine products. To avoid
protecting groups as well as overalkylation, we attempted
using excess of ammonia or adjusting pH through reductive
amination.
Several strategies have already been developed for the
synthesis of milnacipran in their racemic and pure form
[3–6, 18, 19]. However, all these routes were involving the

2
Journal of Chemistry
NH2·HCl
O
N
Scheme 1
Ammonia
NaCNBH3
R
R
NH2
(III)
O
R
R
H
R
N
H
(II)
⊕
(I)
R
O
R
+
H
H
NaCNBH3
N
R
R
N
R
N
R
(IV)
(VI)
(V)
Scheme 2: Reductive amination of aldehydes.
N3
OH
NaN3
PPh3
NH2
H2/pd/C
MeOH
LiNEt2
THF
O
O
N
N
N
O
CBr4
DMF
O
O
Scheme 3
synthesis of the primary amine group through protection and
deprotection. e protection and deprotection of potassium
phthalimide significantly reduce the atom economy, yield,
and increase the impurities as well as number of steps [20, 21].
Some synthetic protocols required special handling and more
precautions, such as lithium amide and hydrogenation. Shuto
et al. reported the synthesis of milnacipran with expensive
and more cautious reagents such as sodium azide and appel
reaction conditions followed by hydrogenation (Scheme 3)
[22, 23]. By the comparison our synthetic route is more reli-
able, more atom economy, and cost effective route with less
by-products.
3. Synthesis of Milnacipran Hydrochloride
e synthesis of milnacipran hydrochloride synthesis starts
with commercially available compound [25] 2. e treatment
of compound 2 with aluminum chloride and diethylamine
at room temperature afforded a ring opening alcohol 3
(Scheme 5). e alcohol compound 3 afer workup directly
proceeded to oxidation with Dess-Martin periodinane
[DMP; 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1-
H)-one]; this reagent has several advantages over chromium
and DMSO-based oxidation reagents that include milder
conditions such as lower temperature, neutral pH, shorter
reaction times, higher yields, simplified workups, high
chemoselectivity, tolerance of sensitive functional groups,
and a longer shelf life time. Oxidation with Swern reagent
is tedious and hazardous; the by-products are dimethyl
To overcome all these issues, we report a practical
synthesis of milnacipran hydrochloride using a combination
of oxidation and reductive amination.
sulfide (Me S), carbon monoxide (CO), and carbon dioxide
2
(CO ). Two of the by-products, dimethyl sulfide and
2
carbon monoxide, are very toxic volatile compounds; due
to low boiling point dimethyl sulfide easily evaporates
into atmosphere; this contributes to the already abundant
pollution in the atmosphere. To overcome these challenges,
Swern oxidation was replaced with the DMP reagent. From
scale up point of view, DMP oxidation is much easier
2. Results and Discussion
Our synthetic strategy is outlined in Scheme 4. e target
primary amine compound 1 could be prepared from com-
mercially available compound [24] (1S∗, 5R∗)-1-phenyl-3-
oxabicyclo[3.1.0] hexane-2-one (2).

Journal of Chemistry
3
NH2·HCl
O
O
O
N
1
2
Scheme 4: Retrosynthesis of milnacipran.
OH
NH2·HCl
CHO
Aq. NH3/NH4OAc
(1) AlCl3
(2) Diethylamine
DMP
O
N
N
O
NaCNBH3
EtOAc. HCl
O
N
O
O
2
4
3
1
Scheme 5
Table 1: Solvent volume optimization.
conditions as indicated in Table 3 and reaction optimization
studied by adding additives like acetic acid and aq. ammonia
solution. As mentioned in the table entry 1 was performed
by adding acetic acid to the reaction, multiple number of
spots was observed in the TLC, based on the theory, the
probable side products were mentioned in the Scheme 6, and
next entries 2 and 3 indicate incremental usage of ammo-
nia gradually shifing towards chemoselctivity of reductive
amination. Entry 4 clearly represents the higher volumes of
ammonia or maintaining pH 12 is the key factor to increase
the chemoselective reductive amination of aldehyde 4.
Second factor is the reaction temperature. Reaction was
not proceeded at RT (entry 1, Table 4) to give desired
primary amine 1. TLC showed reaction stopped at imine step
only. Entry numbers 2 and 3 indicate that gradual increase
in temperature enhances the conversion of compound 1.
70–75∘C range is the optimum temperature for reductive
amination of aldehyde 3.
Entry
1
2
3
4
Reagent
DMP
DMP
DMP
DMP
DCM (mL)
Yield (%)
5
40
60
70
95
10
15
20
Table 2: Reagent mole equivalent optimization table.
Entry
1
2
3
4
DMPb
0.8
0.9
1.0
1.1
Solvent
DCM
DCM
DCM
MDC
Yield%
50
70
83
95
b: Dess-Martin periodinane reagent.
Metal hydride plays the main role in the reduction
during reductive amination; to understand the impact of
than Swern oxidation. Several parameters were selected to
optimize the oxidation reaction, including solvent volumes
and mole equivalents of reagent.
Oxidation of compounds 3 to 4 solvent volumes men-
tioned at Table 1, entries 1, 2, and 3 indicates that less volume
of dichloromethane (DCM) is not favoured for this reaction.
As per entry 4 higher volumes (20 volumes) are optimum for
the DMP oxidation.
mole equivalent of NaCNBH some optimization results were
3
mentioned in Table 5. Entry number 1 indicates that 0.5 eq of
reagent is not good enough to complete reaction; same way
entry numbers 2 and 3 also indicate that this reaction requires
more eq of reagent (NaCNBH ). Entry 4 clearly indicates that
3
reductive amination of aldehyde and ammonia requires 3 eq
of reagent to get maximum conversion of compound 1.
Reaction time is also the important factor to achieve
desired product with highest yield; entry number 1 indicates
1 hr is not enough to complete this reaction; as per Table 6
(entries 2 and 3) 2–4 hrs is also not sufficient for reductive
amination reaction. Reaction time 6 hrs (entry 4, Table 6) was
optimum reaction time to get maximum yield of compound
1.
DMP reagent optimization mentioned in Table 2, entries 1
and 2, shows poor yields due to incomplete reaction, whereas
entry 3 is the optimum amount of reagent to get best results.
Entry 4 also indicates that 1.1 eq of DMP reagent is the
suitable quantity to complete the reaction. Compound 3 was
1
confirmed by H-NMR, significant peak observed at 9.05 ꢀ
ppm for aldehyde.
Reductive amination step depends on the various factors
like number of moles of reagent, pH, reaction time, and
temperature. Reductive amination was tried at different pH
Finally the optimized conditions for the synthesis of
compound 1 from aldehyde 3 were 40 eq of aq. ammonia, 3
eq of sodium cyanoborohydride, 20 volumes of ethanol, and

4
Journal of Chemistry
Aq. NH3/NH4OAc
CHO
NH2
O
NH
NaCNBH3
EtOAc. HCl
O
+
+
O
O
N
N
N
N
4
1
5
O
N
N
O
N
N
O
6
Scheme 6: Overreductive amination.
Table 3: pH of the reaction mixture.
Entry
1
Additive
AcOH
pH
7
Ratioa (1 : 5)
1 : 1
Yield %
40
2
3
4
Aq. NH (5 eq)
8
10
12
4 : 1
10 : 1
20 : 1
50
65
75
3
Aq. NH (10 eq)
3
Aq. NH (40 eq)
3
a: ratios calculated based on TLC profile.
Table 4: Reductive amination reaction temperature.
scale synthesis of milnacipran hydrochloride (1). Charac-
terization of 2-(aminomethyl)-N,N-diethyl-1-phenyl cyclo-
propane carboxamide hydrochloride (1) was done by proton
1HNMR,13C NMR, and mass; significant broad amine peak
is observed at 8.82 ꢀ ppm and disappearance of peak at ∼
9.05 ppm, which is related to corresponding aldehyde peak.
ꢁꢂ/ peak is observed at 247.2 which is M+1 of milnacipran
hydrochloride 1.
We have demonstrated the synthesis of milnacipran hydro-
chloride with an efficient approach. We employed different
conditions to obtain adequate experimental conditions such
as pH, temperature, and sodium cyanoborohydride reagent.
In addition, the employment of reductive amination of alde-
hyde with sodium cyanoborohydride selectively produces
primary amine with high yielding. Finally, we have developed
a mild method for the conversion of the aldehyde into
primary amine using reductive amination method.
Entry
1
2
3
4
Ethanol mL
Temp ∘C
Yield%
No rxn
25
57
75
20
20
20
20
RT
40
55
75
Table 5: NaCNBH mole eq optimization.
3
Temp ∘C
Yield%
28
45
55
75
4. Conclusion
Entry
1
2
3
4
NaCNBH eq
3
0.5
1
2
75
75
75
75
3
Table 6: Reaction∘time optimization.
Entry
1
2
3
4
Reagent
NaCNBH
NaCNBH
NaCNBH
NaCNBH
Temp C
Rxn time (h)
Yield%
28
45
55
75
75
75
75
75
1
3
3
3
3
2
4
6
5. Experimental Section
5.1. Synthesis of (1S,2R)-1-Phenyl-2-(hydroxymethyl)-N,N-die-
thyl Cyclopropane Carboxamide (3). Aluminum chloride
(22 g) was suspended in (150 mL) CH Cl and diethylamine
6-7 hrs reaction time with saturated solution of ammonium
acetate. Based on optimized conditions, we attempted gram
2
2

Journal of Chemistry
5
(25 g) was then added under stirring at room tempera-
ture, slowly cooled to 0–5∘C, and stirred for 10 minutes,
and the RM temperature was raised to 10–15∘C; 20 gm
of cis( )1-phenyl-3-oxabicyclo[3.1.0]hexane-2-one was dis-
solved in CH Cl (50 mL) and added to the reaction mass
References
[1] J. Deregnaucourt and R. Grosse, WO Patent, 2004075886, 2003.
[2] L. Mansuy, WO Patent, 2009127737, 2008.
[3] G. Mouzin, H. Cousse, and B. Bonnaud, “A convenient synthesis
of bifunctional vicinal cyclopropanes,” Synthesis, vol. 4, pp. 304–
305, 1978.
[4] S. Shuto, H. Takada, D. Mochizuki et al., “( )-(Z)-2-(amino-
methyl)-1-phenylcyclopropanecarboxamide derivatives as a
new prototype of NMDA receptor antagonists,” Journal of
Medicinal Chemistry, vol. 38, no. 15, pp. 2964–2968, 1995.
2
2
for 1 hour at 10–15∘C. e temperature of the reaction mass
was raised at room temperature and stirred for 1 hour. Afer
completion of the reaction, the reaction mass was quenched
in ice-cooled water (140 mL). e organic layer was collected
and washed with water and hydrochloric acid. Aqueous layer
was back extracted with CH Cl (2 × 100 mL); combined
2
2
organic layer was directly taken as such for the next step.
[5] M. Zhang and P. E. Eaton, “BuMgNiPr : a new base for sto-
2
ichiometric, position-selective deprotonation of cyclopropane
carboxamides and other weak CH acids,” Angewandte Chemie
International Edition, vol. 41, no. 12, pp. 2169–2171, 2002.
5.2. Synthesis of (1S,2R)-1-Phenyl-2-formyl-N,N-diethyl Cyclo-
propane Carboxamide (4). To a solution of 3 (1 eq) in CH Cl
2
2
[6] K. Vervisch, M. D. Hooghe, K. W. Tornoos, and N. De Kimpe, “A
new approach towards 1-phenyl and 1-benzyl substituted 2-
(aminomethyl)cyclopropanecarboxamides as novel derivatives
of the antidepressant Milnacipran,” Organic & Biomolecular
Chemistry, vol. 7, pp. 3271–3279, 2009.
[7] F. Kagan, M. A. Rebenstorf, and R. V. Heinzelman, “e pre-
paration of glycamines,” Journal of the American Chemical
Society, vol. 79, no. 13, pp. 3541–3544, 1957.
[8] A. Lauritsen and R. Madsen, “Synthesis of naturally occurring
iminosugars from d-fructose by the use of a zinc-mediated
fragmentation reaction,” Organic and Biomolecular Chemistry,
vol. 4, no. 15, pp. 2898–2905, 2006.
[9] S. K. Sharma, M. F. Songster, T. L. Colpitts, P. Hegyes, G. Barany,
and F. J. Castellino, “Reductive amination with tritylamine as an
ammonia equivalent: efficient preparation of the 5-[4-[[(9-
fluorenylmethyloxycarbonyl)-amino]methyl]-3,5-dimethoxy-
phenoxy]valeric acid (PAL) handle for peptide synthesis,”
Journal of Organic Chemistry, vol. 58, no. 18, pp. 4993–4995,
1993.
[10] H. Katayama, T. Utsumi, C. Ozawa, Y. Nakahara, H. Hojo, and
Y. Nakahara, “Pyruvoyl, a novel amino protecting group on
the solid phase peptide synthesis and the peptide condensation
reaction,” Tetrahedron Letters, vol. 50, no. 7, pp. 818–821, 2009.
[11] M. Kojima, Y. Nakamura, A. Nakamura, and S. Takeuchi, “Total
synthesis of cucurbitoside A using a novel fluorous protecting
group,” Tetrahedron Letters, vol. 50, no. 8, pp. 939–942, 2009.
[12] A. Ali, R. J. B. H. N. van den Berg, H. S. Overkleef, D. V. Filip-
pov, G. A. van der Marel, and J. D. C. Code´e, “Methylsulfonyl-
ethoxycarbonyl (Msc) and fluorous propylsulfonylethoxycar-
bonyl (FPsc) as hydroxy-protecting groups in carbohydrate
chemistry,” Tetrahedron Letters, vol. 50, no. 19, pp. 2185–2188,
2009.
[13] M. S. M. Timmer, B. L. Stocker, P. T. Northcote, and B. A.
Burkett, “Az-a colourful azulene-derived protecting group,”
Tetrahedron Letters, vol. 50, no. 51, pp. 7199–7204, 2009.
(400 mL) was added Dess-Martin periodinane (1.1 eq) at RT
and the resulting solution was stirred for 2 hours at RT. e
reaction mixture was quenched with a saturated solution
of Na SO and NaHCO ; the reaction mixture was passed
2
3
3
through a pad of celite. e combined organic phase was
dried over anhydrous Na SO , concentrated, and purified by
2
4
column chromatography (silica gel : AcOEt/hexane, 1 : 2) to
give 4 as a white solid (95%). 1H-NMR: (400 MHz, CDCl )
3
ꢀ: 0.69 (3H, t, ꢃ = 7.0 Hz), 1.11 (3H, t, ꢃ) 7.0 Hz), 1.71 (1H, dd,
ꢃ) 5.5, 8.5 Hz), 2.28 (1H, dd, ꢃ = 5.5, 6.0 Hz), 2.50 (1H, ddd,
ꢃ = 6.0, 6.0, 8.5 Hz), 3.18 (1H, dq, ꢃ = 14.0, 7.0 Hz), 3.26 (1H,
dq, ꢃ = 14.0, 7.0 Hz), 3.42 (1H, dq, ꢃ = 14.0, 7.0 Hz), 3.46 (1H,
dq, ꢃ) 14.0, 7.0 Hz), 7.23–7.38 (5H, m), 9.05 (1H, d, ꢃ = 6.0 Hz).
LC-MS 246.26 (M+1) peak found with purity 98%.
5.3. Synthesis of 2-(Aminomethyl)-N,N-diethyl-1-phenyl Cyclo-
propane Carboxamide Hydrochloride (1). To a solution of 4
(1.0 eq) in a saturated solution of NH OAc in ethanol (20 mL)
4
were added NaCNBH (3 eq) and 30% aqueous ammonia
3
(8 mL). e mixture was stirred at reflux for 6 hrs, cooled to
RT, and concentrated under reduced pressure to get crude
product. Ethyl acetate hydrochloride was added to the crude
product; corresponding hydrochloride salt was isolated and
filtered under vacuum to get 1 as a crystal (23 g, 70%). Mp
178–180∘C. 1H NMR: (CDCl , 400 MHz) ꢀ: 0.90 (t, 3H, ꢃ =
3
7.2 Hz), 1.11 (t, 3H, ꢃ = 7.2 Hz), 1.76–1.83 (m, 2H), 2.45 (m,
1H), 3.35–3.40 (m, 4H), 3.73–3.76 (m, 1H), 7.10–7.29 (m, Ar,
5H), 8.82 (br, s, 2H); 13C NMR: (CDCl , 100 MHz) ꢀ: 11.9 (1C,
3
CH3), 12.6 (1C, CH3), 17.8 (1C, CH2), 24.9 (1C, CH), 39.2 (1C,
N-CH2), 41.66 (1C, N-CH2), 42.4 (1C, N-CH2), 125.4 (Ar,
2C), 126.7 (Ar, 1C), 128.5 (Ar, 2C), 138.1 (Ar, 1C), 170.1 (1C,
amide); ꢁꢂ/: 247.2 (M+1).
[14] B. M. Trost, “e atom economy—a search for synthetic
Conflicts of Interest
efficiency,” Science, vol. 254, no. 5037, pp. 1471–1477, 1991.
[15] R. F. Borch, M. D. Bernstein, and H. D. Durst, “Cyanohydrido-
borate anion as a selective reducing agent,” Journal of the
American Chemical Society, vol. 93, no. 12, pp. 2897–2904, 1971.
e authors declare that there are no conflicts of interest.
Acknowledgments
[16] P. Bowles, J. Clayden, M. Helliwell, C. McCarthy, M. Tomkin-
son, and N. Westlund, “Atroposelectivity in the reactions of
ortholithiated aromatic tertiary amides with aldehydes,” Journal
of the Chemical Society—Perkin Transactions 1, no. 17, pp. 2607–
2616, 1997.
e authors are grateful to the Management of Nify Labs
Pvt. Limited, Hyderabad, for supporting this work and
cooperation from other colleagues also is highly appreciated.

6
Journal of Chemistry
[17] A. Pelter, R. M. Rosser, and S. Mills, “Reductive aminations of
ketones and aldehydes using borane-pyridine,” Journal of the
Chemical Society, Perkin Transactions 1, pp. 717–720, 1984.
[18] B. Bonnaud, G. Mouzin, H. Cousse, and J. F. Patoiseau, Euro-
pean Patent Publication 0200638, 1986.
[19] M. Nicolas, P. Hellier, C. Diard, and L. Subra, European Patent
Publication 2391599, 2010.
[20] J. Alliot, E. Gravel, F. Pillon, D.-A. Buisson, M. Nicolas, and E.
Doris, “Enantioselective synthesis of levomilnacipran,” Chemi-
cal Communications, vol. 48, no. 65, pp. 8111–8113, 2012.
[21] E. M. Dangerfield, C. H. Plunkett, A. L. Win-Mason, B. L.
Stocker, and M. S. M. Timmer, “Protecting-group-free synthesis
of amines: synthesis of primary amines from aldehydes via
reductive amination,” Journal of Organic Chemistry, vol. 75, no.
16, pp. 5470–5477, 2010.
[22] S. Shuto, S. Ono, Y. Hase, N. Kamiyama, and A. Matsuda, “Syn-
thesis of (+)- and (-)-milnaciprans and their conformationally
restricted analogs,” Tetrahedron Letters, vol. 37, no. 5, pp. 641–
644, 1996.
[23] S. Shuto, S. Ono, H. Imoto, K. Yoshii, and A. Matsuda, “Syn-
thesis and biological activity of conformationally restricted
analogues of milnacipran: (1S,2R)-1-phenyl-2-[(R)-1-amino-2-
propynyl]-N,N- diethylcyclopropanecarboxamide is a novel
class of NMDA receptor channel blocker,” Journal of Medicinal
Chemistry, vol. 41, no. 18, pp. 3507–3514, 1998.
[24] P. R. Gopal, A. C. Prabakar, E. R. R. Chandrashekar, B. V.
Bhaskard, and P. V. Somaiah, “Synthesis and characterization
of process related impurities of ( )-Milnacipran,” Journal of the
Chinese Chemical Society, vol. 60, no. 6, pp. 639–644, 2013.
[25] S. Shuto, S. Ono, Y. Hase et al., “Conformational restriction by
repulsion between adjacent substituents on a cyclopropane ring:
design and enantioselective synthesis of 1-phenyl-2-(1-ami-
noalkyl)-N,N-diethylcyclopropanecarboxamides as potent
NMDA receptor antagonists,” Journal of Organic Chemistry,
vol. 61, no. 3, pp. 915–923, 1996.

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