An Improved Synthesis of Amantadine Hydrochloride

Article abstract of DOI:10.1021/acs.oprd.7b00242

Amantadine hydrochloride 1 is an antiviral drug used in the prevention and treatment of influenza A infections. It has also been used for alleviating early symptoms of Parkinson's disease. Several methods for the preparation of 1 have been reported. These procedures started with adamantane 2 using as many as four reaction steps to produce amantadine hydrochloride with overall yields ranging from 45% to 58%. In this article, we describe a two-step procedure for the synthesis of 1 from 2 via N-(1-adamantyl)acetamide 4 with an improved overall yield of 67%. The procedure was also optimized to reduce the use of toxic solvents and reagents, rendering it more environment-friendly. The procedure can be considered as suitable for large-scale production of amantadine hydrochloride. The structure of amantadine hydrochloride was confirmed by ¹H NMR, ¹³C NMR, IR, and MS.

Full text of DOI:10.1021/acs.oprd.7b00242

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Full Paper
AN IMPROVED SYNTHESIS OF AMANTADINE HYDROCHLORIDE
Duong Binh Vu, Thinh Van Nguyen, Son Trung Le, and Chau Dinh Phan
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00242 • Publication Date (Web): 28 Sep 2017
Downloaded from http://pubs.acs.org on September 28, 2017
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AN IMPROVED SYNTHESIS OF AMANTADINE
HYDROCHLORIDE
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1
1
1
2*
Duong Binh Vu , Thinh Van Nguyen , Son Trung Le and Chau Dinh Phan
1
Vietnam Military Medical University, No.160, Phung Hung str., Phuc La ward, Ha Dong district,
Hanoi, Vietnam.
2
School of Chemical Engineering, Hanoi University of Science and Technology, No.1, Dai Co Viet
str., Bach Khoa ward, Hai Ba Trung district, Hanoi, Vietnam.
*
Corresponding Author: chau.phandinh@hust.edu.vn
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KEYWORDS: Amantadine hydrochloride, adamantane, Nꢀ(1ꢀadamantyl)acetamide, Ritter,
antiviral, antidyskinetic.
ABSTRACT: Amantadine hydrochloride 1 is an antiviral drug used in prevention and treatment of
influenza A infections. It has also been used for alleviating early symptoms of Parkinson’s disease.
Several methods for the preparation of 1 have been reported. These procedures started with
adamantane 2 using as many as four reaction steps to produce amantadine hydrochloride with
overall yields ranging from 45% to 58%. In this article, we describe a twoꢀstep procedure for the
synthesis of 1 from 2 via Nꢀ(1ꢀadamantyl)acetamide 4 with an improved overall yield of 67%. The
procedure was also optimized to reduce the use of toxic solvents and reagents, rendering it more
environmentꢀfriendly. The procedure can be considered as suitable for largeꢀscale production of
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1
amantadine hydrochloride. The structure of amantadine hydrochloride was confirmed by HꢀNMR,
1
3
CꢀNMR, IR and MS.
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INTRODUCTION
Amantadine hydrochloride 1 is an antiviral drug used to treat influenza A infections. Its antiviral
1
activity was first reported in 1964 by Davies W.L. et al. A few years later, the drug received FDA
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approval as a preventative for Asian influenza and influenza A infections. In addition to its use as
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an antiviral medication, amantadine hydrochloride has been utilized for alleviating early symptoms
2
of Parkinson’s disease and treating dyskinesia.
There have been a number of publications about the synthesis of amantadine 5 and amantadine
3
aꢀo
3aꢀe
hydrochloride 1 using one of the following raw materials: adamantane 2, 1ꢀbromoadamantane
3
fꢀh
3i
3jꢀk
3lꢀn
3,
1ꢀadamantanecarboxylic acid, 1ꢀadamantanol,
1ꢀadamantylꢀmagnesiumꢀbromide
and
3o
tetrahydrodicyclopentadiene.
Several groups have reported the synthesis of 1 from 2 via four steps with relatively low
3
a,3c,3f
yields,
whereby bromination or nitration of 2 produces 3 or 1ꢀadamantyl nitrate, respectively.
Conversion of 3 to 4 in the presence of concentrated sulfuric acid and acetonitrile followed by
o
treatment with sodium hydroxide and polyethylene glycol (PEG) at reflux conditions (240ꢀ250 C)
yields 5. Finally, salt formation between 5 and anhydrous HCl in ether solution produces 1 with
3
a, 3c
overall yields varying from 45 to 58% (Scheme 1).
Scheme 1. Fourꢀstep synthesis of amantadine hydrochloride 1 from adamantane 2
Reagents and conditions: (a) Br , CHCl , reflux; (b) CH CN, H SO , rt, 12 h, benzene extraction; (c) NaOH,
DEG, reflux, 15 h; (d) anhydrous HCl, ether.
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In order to make these procedures suitable for largeꢀscale production of amantadine hydrochloride
, several issues should be addressed. First, the bromination step (a) carried out under reflux can
1
lead to the emission of toxic bromine vapor. Second, 1ꢀbromoadamantane 3 is sensitive to moisture,
4
and thus not suitable for longꢀterm storage. Third, some solvents used in these procedures, such as
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3c, 4
benzene and diethylene glycol (DEG), are toxic.
DEG can also decompose exothermally when
°
4
heated to 240ꢀ250 C, releasing explosive hydrogen gas and acid smoke. Finally, using ether as a
solvent for amantadine extraction and subsequent hydrochloride formation is a matter of concern
3
aꢀc,3f
because of its high flammability and tendency to form peroxides.
Other groups have also described the synthesis of 1 from 2 via two steps, whereby 4 was prepared
from 2 in one step using one of the following reactants: molybdenum hexacarbonyl,
5
a
5bꢀf
bromotrichloromethane, oleum or fuming H SO . However, these reagents are either expensive
2
4
or toxic, rendering the described methods unfavorable for largeꢀscale production of 1. In this article,
we report an improved method for the synthesis of 1 from 2 via two steps.
RESULTS AND DISCUSSION
In this report, compound 4 was identified as a suitable intermediate to prepare 1 via a oneꢀstep
acetamidation of 2 in concentrated sulfuric acid and acetonitrile. Hydrolysis of 4 in a mixture of
o
potassium hydroxide, propylene glycol (PG) and water at 125ꢀ130 C yields 5, which on treatment
with 5N aq. HCl produces 1. Direct conversion of 2 to 4 is the key step in the synthesis of 1 (Scheme
2
).
Scheme 2. Twoꢀstep synthesis of amantadine hydrochloride 1 from adamantane 2
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Reagents and conditions: (a) 98% H SO , 99.5% CH CN, 55ꢀ65 C, 4.5 h; (b) (i) 82% KOH, water, PG, 125ꢀ
2
4
3
o
1
30 C, 7.5 h, CH Cl extraction, (ii) 5N aq. HCl.
2 2
Synthesis of N-(1-adamantyl)acetamide 4. Compound 4 was prepared from 2 in one step via the
Ritter reaction. In this reaction, concentrated sulfuric acid induced the addition of a nitrile (−C≡N) to
the carbenium ion of 2, which on treatment with water produces 4. This method bypassed the
bromination or nitration of 2 (Scheme 1, step a), thus eliminating the need for liquid bromine or
fuming nitric acid. In addition, the molar ratio between reactants was optimized to reduce the use of
concentrated sulfuric acid (see Table S1-4). Finally, dichloromethane was used as the alternative
solvent to benzene for isolation and separation of 4. This change reduced the toxicity level of the
described procedure.
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Synthesis of amantadine hydrochloride 1. Compound 5 was synthesized in a mixture of water,
propylene glycol (PG) and potassium hydroxide instead of sodium hydroxide in diethylene glycol
(
DEG). The molar ratio between water, propylene glycol (PG), potassium hydroxide and 4 was also
optimized for deacetylation (see Table S5-8), which resulted in a lower reaction temperature (125ꢀ
o
o
3c
1
30 C) and a shorter reaction time (8.5 h) than described previously (i.e. 240ꢀ245 C; 15 h).
Finally, the synthesis of 1 from 5 utilized 5N aq. HCl in place of anhydrous HCl in ether solution to
reduce the risk of explosion from ether.
In summary, Scheme 2 presents a safe, economically competitive and environmentally friendly
synthesis of 1. Compound 1 was obtained in two steps with a high overall yield of 67% (compared
to overall yields of 45ꢀ58% in four steps). Raw materials and reagents used in our procedure are
inexpensive and commercially available. Each reaction step was optimized to reduce or eliminate
the use of toxic reagents and solvents. Total preparation time was significantly reduced compared to
those methods described previously. Our results suggest that this method is economically
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advantageous over the earlier reported approaches owing to its high yields and the use of less
expensive raw materials.
CONCLUSION
An improved synthesis for amantadine hydrochloride 1 has been provided. It produces a total
yield of 67% over two steps and a purity of 99%. The synthesis of 4 from 2 was successfully
accomplished in one step via the Ritter reaction. This method does not require liquid bromine or
fuming nitric acid as reactants. The subsequent conversion of 4 to 5, and then 5 to 1, was carried out
under milder reaction conditions without using hazardous solvents. These advantages facilitate the
efficient, costꢀeffective and industrially convenient production of amantadine hydrochloride.
EXPERIMENTAL SECTION
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General Procedures. All of the commercially available reagents and solvents were used without
1
13
further purification. The HꢀNMR and CꢀNMR spectra were measured in CDCl on BrukerꢀAV500
3
spectrometer; the chemical shifts are reported in ppm relative to TMS. The IR spectra were recorded
in the solid state as KBr dispersion using a GXꢀPerkin Elmer spectrophotometer (USA). The mass
spectra (70 eV) were recorded on AutoSpec Premier Spectrometer. The melting points were
measured on Stuart SMPꢀ10 apparatus. Analytical thin layer chromatography (TLC) was carried out
on Merck preꢀcoated aluminum silica gel sheets (Kieselgel 60Fꢀ254).
N-(1-adamantyl)acetamide (4). To a mixture of 99.5% acetonitrile (400 mL, 7.66 mol) and 98%
adamantane 2 (277g, 2.0 mol) was added dropwise 98% sulfuric acid (1.56 L, 28.4 mol) with
o
o
stirring at 25ꢀ30 C for 2 h. The reaction mixture was stirred at 60ꢀ65 C for an additional 2.5 h. At
the end of the reaction, ice water (5.00 L) was added to the reaction mixture and stirred for 1.0 h at
o
0
ꢀ5 C. The resulting mixture was then extracted with dichloromethane (8.00 L); the separated
o
organic layer was washed with cold water (0ꢀ5 C) and dried over Na SO . The solvent was removed
2
4
under vacuum to yield 4 as a white solid. Yield: 314 g (82%). Purity (GC): 99.20%, t 15.90 min;
R
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mp 147ꢀ149 C. HꢀNMR (CDCl 500 MHz): δ 5.45 (s, 1H), 2.06 (s, 3H), 2.00 (s, 6H), 1.91 (s, 3H),
3
,
13
1
.67 (s, 6H). CꢀNMR (CDCl , 125 MHz): δ 169.32, 51.78, 41.58, 36.35, 29.41, 24.59. IR (KBr):
3
ꢀ1
+
cm 3277.04 (NꢀH); 2900.03ꢀ2849.76 (CꢀH); 1643.57 (C=O). MS: m/z = 194.0 [M+1] , 151.9 [Mꢀ
+
+
COCH +1] , 135.0 [MꢀNHCOCH ] .
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Amantadine hydrochloride (1). A mixture of 82% potassium hydroxide (600 g, 8.74 mol), water
(100 mL) and propylene glycol (750 mL) was stirred at room temperature for 1 h, to which was
o
o
added 4 (290 g, 1.5 mol). The mixture was maintained at 125 Cꢀ130 C for 8.5 h, then cooled to
room temperature and followed by the addition of iceꢀcold water (2.00 L). The reaction mixture was
extracted with dichloromethane (3 x 2.00 L). The separated organic layer was concentrated by threeꢀ
o
fold. To the concentrate was added 5N aq. HCl (1.40 L), stirred at 55ꢀ60 C for 1 h, and then cooled
to room temperature. The resulting aqueous layer was evaporated under vacuum to give a white
o
o
solid, to which was added acetone (200 mL), stirred at 50 C for 1 h, and then at 0ꢀ5 C for additional
h. The obtained colorless precipitate was filtered off and dried under vacuum to give 1. Yield: 232
g (82%). R = 0.5 (CHCl /MeOH/25% aqueous NH = 6:1:1). Purity (GC): 99.22%, t 10.10 min; mp
1
f
3
3
R
o
1
13
3
60 C. HꢀNMR (CDCl , 500 MHz): δ 8.28 (br, s, 3H), 2.15 (s, 3H), 2.04 (s, 6H); 1.69 (s, 6H). Cꢀ
3
ꢀ1
NMR (CDCl , 125 MHz): δ 52.95, 40.56, 35.38, 28.97. IR (KBr): cm 3331.73ꢀ3185.17 (NꢀH);
3
+
+
3054.60ꢀ2917.82 (CꢀH); 1363.50 (CꢀN). MS: m/z = 151.9 [M +1] , 135.0 [MꢀNH ꢀ1] .
2
Supporting Information Available: Experimental procedures and analytical data (NMR, IR, MS
and GC) for compounds 4 and 1. This material is available free of charge via ACS Publications
website at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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*
Eꢀmail: chau.phandinh@hust.edu.vn
ORCID
Chau Dinh Phan: 0000ꢀ0002ꢀ 4232ꢀ7023
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Present Addresses
1
1
1
2*
Duong Binh Vu , Thinh Van Nguyen , Son Trung Le and Chau Dinh Phan
1
Vietnam Military Medical University, No.160, Phung Hung str., Phuc La ward, Ha Dong district,
Hanoi, Vietnam.
2
School of Chemical Engineering, Hanoi University of Science and Technology, No.1, Dai Co Viet
str., Bach Khoa ward, Hai Ba Trung district, Hanoi, Vietnam.
Author Contributions
The manuscript was written with contributions from all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
This research was conducted at the Research Center for Drug Manufacturing Application and
financially supported by project no. CNHD.DT.063/15ꢀ17, Vietnamese National Program for the
Development of Pharmaceutical Chemistry, period 2006ꢀ2020.
ACKNOWLEDGMENTS
We gratefully acknowledge the assistance of Mr. Dang Vu Luong, Institute of Chemistry, VAST
for the MS and NMR spectral analyses.
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