ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
020, VOL. 52, NO. 1, 77–80
2
OPPI BRIEF
A Simple Process for the Synthesis of 1-Aminoadamantane
Hydrochloride
a
b
a
c
Van Hien Pham
, Thi Hang Tran , Binh Duong Vu , Huy Binh Le , Huu Tung
c
b
Nguyen , and Dinh Chau Phan
a
b
Drug Research and Development Center, Vietnam Military Medical University, Hanoi, Vietnam; School
c
of Chemical Engineering, Hanoi University of Science and Technology, Hanoi, Vietnam; Phenikaa
Research and Technology Institute (PRATI), A&A Green Phoenix Group, Hanoi, Vietnam
ARTICLE HISTORY Received 14 July 2019; Accepted 30 July 2019
1
-Aminoadamantane hydrochloride (amantadine hydrochloride, 1) is an antiviral drug,
1
first reported in 1964, used to treat certain influenza A virus infections. It was
approved by the United States Food and Drug Administration in 1966. It has been
2
used to treat influenza A infection in the Asian influenza epidemic. It is also used as an
3
antidyskinetic agent to treat Parkinson’s disease.
A number of publications reported the synthesis of amantadine (5) or amantadine
4
–15
hydrochloride (1), using different starting materials, including adamantane,
1-bro-
1-adamantyl-
Several groups have
16–19
20,21
22,23
moadamantane,
magnesium-bromide,
reported the synthesis of amantadine (5) and amantadine hydrochloride (1) from 2 or
1-adamantanecarboxylic acid,
1-adamantanol,
2
4–26
27
and tetrahydrodicyclopentadiene.
4
1
6
3
in three or four steps (Scheme 1). The overall yield of these procedures varied from
4
,16
48 to 58%.
Along with their merits, these procedures also have several disadvantages, including
the use of toxic reagents or solvents and fire or detonation hazards associated with
scale-up and high temperatures. We now demonstrate (Scheme 2) that 1 can be synthe-
sized from 3 in only in two steps in higher relative overall yield and limited use of toxic
ꢀ
reagents. Compound 6 was prepared from 3 in one step, using formamide at 140 C for
3
hours. The simple work-up procedure consisted of adding the reaction mixture to ice-
cold water, filtration of the precipitated white solid and washing with cool water.
Product 6 thus obtained was recrystallized from methanol-water, then hydrolyzed using
3
6% aq. HCl in ethanol to give 1 of purity greater than 99% (see experimental section).
In summary, a simple and economical synthesis of 1 has been provided, which is
suitable for work at hectogram scale. It produces a total yield for 1 of 85% and a purity
greater than 99% over two steps. This method does not require the use of large amounts
of sulfuric or nitric acid and avoids the use of toxic or otherwise hazardous solvents.
These advantages facilitate the efficient, cost-effective and industrially convenient pro-
duction of 1, and we hope this method will stimulate further research into these useful
materials for the preparation of antivirals.
CONTACT Binh Duong Vu
Medical University, 100000, Hanoi, Vietnam; Dinh Chau Phan
Drug Research and Development Center, Vietnam Military
Engineering, Hanoi University of Science and Technology, No. 1, Dai Co Viet str., Bach Khoa ward, Hai Ba Trung district,
Hanoi, 100000, Vietnam
ß 2020 Taylor & Francis Group, LLC
Le, Huy Binh
