A PROCESS FOR THE PREPARATION OF 1,2,4-TRIOXOLANE
ANTIMALARIALS
Field of the Invention
This invention relates to an improved process for the preparation of compounds of
Formula I, salts of the free base cw-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl propyl)
amino] carbonyl] methylj-l', 2', 4'-trioxaspiro [4.5] decane,
7(V / " o ' V ^ O , HX
H \X,
H
Formula I
wherein X is an anion. The compounds of Formula I have antimalarial activity.
Background of the Invention
Malaria is an acute and often chronic infectious disease resulting from the presence of
protozoan parasites within red blood cells. Caused by single-celled parasites of the genus
Plasmodium, malaria is transmitted from person to person by the bite of female mosquitoes.
The discovery of artemisinin (qinghaosu), a naturally occurring endoperoxide
sesquiterpene lactone, triggered substantial efforts to elucidate its molecular mechanism of
action and to identify novel antimalarial peroxides (Dong and Veimerstrom, Expert Opin.
Ther. Patents H., 1753-1760, (2001)). Many synthetic 1, 2, 4-trioxanes, 1,2, 4, 5-tetraoxanes,
and other endoperoxides have been prepared.
A synthetic procedure for preparing compounds of Formula I, salts of the free base
d5-adamantane-2-spiro-3'-8'-[[r(2'-amino-2'-methyl propyl) amino] carbonyl] methyl]-!',
2', 4'-trioxaspiro [4.5] decane has been disclosed in U.S. Patent No. 6,906,205. WO
2007138435 also discloses a synthetic procedure for preparing compounds of Formula I. The
free base obtained by this procedure involves the formation of dimer impurity, which affects
the purity of the free base.
Therefore, there is a need to develop a process which provides the free base of high
purity.
2
Summary of the Invention
In one aspect, the present invention provides an improved, economically attractive
and an easily operable process, which results in reduced solvent usage.
In another aspect, the present invention provides an improved process for the
preparation of compounds of Formula I, salts of the free base cw-adamantane-2-spiro-3'-8'-
[[[(2'-amino-2'-methyl propyl) amino] carbonyl] methyl]-!', 2', 4'-trioxaspiro [4.5] decane,
H ^ / ^ ^ - \ ^'^"^
< O o ^ r .Hx
H
Formula I
in high yield, wherein X is an anion, for example, acetate, adipate, alginate, citrate, aspartate,
benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate,
glycerophosphate, glycolate, malonate, hemisulfate, heptanoate, hexanoate, fumarate,
hydrochloride, hydrobromide, hydroiodide, isethionate. lactate, maleate, methane sulfonate,
nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-
phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,
glutamate,. bicarbonate, ,p-toluene sulfonate, or undecanoate, wherein the freebase which is
used has high purity.
In another aspect, the present invention provides an improved process for the
preparation of free base, cw-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl propyl) amino]
carbonyl] methyl]-l', 2', 4'-trioxaspiro [4.5] decane, of Formula III, having high purity.
y
H V>(
H
Formula III
The term "high purity" refers to purity (HPLC) not less than 96%.
In another aspect, the present invention provides an improved process for the
preparation of free base, cw-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl propyl) amino]
carbonyl] methyl]-!', 2', 4'-trioxaspiro [4.5] decane, having no dimer impurity of Formula
IV.
3
H O O H
Formula IV
Detailed Description of the Invention
The process for the preparation of free base, c/5'-adamantane-2-spiro-3'-8'-[[[(2'-
amino-2'-methyl propyl) amino] carbonyl] methyl]-!', 2', 4'-trioxaspiro [4.5] decane,
comprises the reaction of the compound of Formula II
A V / o ^^^ o
H v><^
H
Formula II
with an activating agent, for example, methyl chloroformate, ethyl chloroformate, propyl
chloroformate, n-butyl chloroformate, isobutyl chloroformate or pivaloyl chloride leading to
the formation of mixed anhydride, which is either reacted in situ reaction with 1,2-diamino-2-
methylpropane, or mixed anhydride is isolated and is reacted with 1,2-diamino-2-
methylpropane, to give free base of Formula III.
H v><,
H
Formula III
With an objective of avoiding the fomiation of dimer impurity during the formation of
free base, different reaction conditions including various combinations of solvents or
different volumes of solvents and/or different amounts of 1, 2-diamino-2-methylpropane
were used.
When 1.8-3 mole equivalents of 1, 2-diamino-2-methylpropane were used in 20- 80
times w/v of dual solvent system of dichloromethane and ethanol (in the ratio of 1:1 v/v), free
base having no dimer impurity was obtained.
4
The reaction of a compound of Formula il with an activating agent and 1,2-diamino-
2-methylpropane can be carried out in the presence of an organic base, for example, trimethyl
amine, triethyl amine, isopropyl amine or mixture(s) thereof
The compound of Formula III on reaction with an acid of Formula HX (wherein X
can be the same as defined earlier) gives compounds of Formula I.
The reaction of a compound of Formula III with an acid of Formula HX to give a
compound of Formula I can be carried out in a solvent, for example, an alcoholic solvent, for
example, methanol, ethanol or isopropanol, hydrocarbon solvent, for example, hexane or
heptane or mixture(s) thereof.
Compound of Formula II can be prepared by following the procedures given in
WO2007138435.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are
included within the scope of the present invention. The examples are provided to illustrate
particular aspects of the disclosure and do not limit the scope of the invention.
EXAMPLES
Example 1: Preparation of (Is, 4s)-dispiro [cyclohexane-l, 3'-[l,2.4] trioxolane-5\ 2"-
tricyclo [3.3.1.1^'^] decani-4-vlacetic acid
The title compound was prepared by following the procedure given in WO 07138435.
Example 2 (a): Preparation of c/5-adamantane-2-spiro-3'-8'-rrr(2'-amino-2'-methvl propvl)
amino] carbonyll methvll-T, 2\ 4'-trioxaspiro [4.5] decane
(\s, 4s)-dispiro [cyclohexane-1, 3'-[l,2,4] trioxolane-5', 2"-tricyclo [3.3.1.1 ' ] decan]-
4-ylacetic acid (10 gm, 31 mmol, 1 equiv) (example 1) was taken in dichloromethane (100
ml) at room temperature under dry nitrogen atmosphere. Tri ethylamine (6.9 ml, 49.6 mmol,
1.6 equiv) was added at room temperature. The reaction mixture was cooled to - 10°C. Ethyl
chloroformate (3.36 gm, 31 mmol, 1 equiv) was added slowly at - 10 to -5°C, under stirring.
The mixture was stirred for about 20 -30 minutes. The resulting mixed anhydride reaction
mixture was added drop wise at -10 to -5°C to a previously prepared solution of 1,2-diamino-2-
methylpropane (this solution was prepared by adding 1,2 - diamino-2-methylpropane (5.47 gm,
62 mmol, 2 equiv) to ethanol (100 ml) at room temperature and it was cooled to - 10°C). The
temperature of reaction mixture was raised to room temperature. The organic layer was
concentrated at 35 to 40°C under reduced pressure to get a thick oily mass. Dichloromethane
5
(200 ml) was added at room temperature under stirring. Deionized (DI) water (100 ml) was
added at room temperature under stirring. The reaction mixture was stirred at room temperature
for about 30 minutes and settled for about 30 minutes at room temperature. The organic layer
was separated. It was washed with 100 ml of saturated sodium bicarbonate solution. The layer
was settled for about 30 minutes and the organic layer was separated. The organic layer was
washed with 50 ml of DI water at room temperature. The layer was settled for about 30 minutes
and the organic layer was separated. The organic layer was concentrated at 35 to 40°C under
reduced pressure. Hexane (100 ml) was added and the reaction mass was stirred at 35 to 40°C
for about 30 minutes and cooled to room temperature. The solid was filtered and washed with
hexane (10 ml). The material obtained was dried at room temperature under reduced pressure
for about 3 h till constant weight was obtained.
Yield: 11.3 gm (1.13 w/w), 92.81%
Mass 393, HPLC Purity 97.86%,
'HNMR (400 MHz, DMSO-de): 5 0.92 (s, 6H), 1.10 - 1.07 (m, 2H), 1.89-1.64 (m, 21H), 2.03
- 2.01 (d,2H), 2.93 (d,2H).
Example 2 (b): Preparation of c/5-adamantane-2-spiro-3'-8'-|"[|"(2'-amino-2'-methvl propyl)
amino] carbonyl] methyl]-!', 2\ 4'-trioxaspiro [4.5] decane
(\s, 4s)-dispiro [cyclohexane-1, 3'-[l, 2, 4] trioxolane-5', 2"-tricyclo [3.3.l.l^'^]
decan]-4-ylacetic acid (15 gm, 46 mmol, 1 equiv) (example 1) was taken in dichloromethane
(150 ml) at room temperature under dry nitrogen atmosphere. Tri ethylamine (13.0 ml, 93
mmol, 2.0 equiv) was added at room temperature. The reaction mixture was cooled to - 10°C.
Ethyl chloroformate (5.55 gm, 51 mmol, 1.1 equiv) was added slowly at - 10 to -5°C, under
stirring. The mixture was stirred for about 30-45 minutes. The resulting mixed anhydride
reaction mixture was added dropwise at -10 to -5°C to a previously prepared solution of 1,2-
diamino-2-methylpropane (this solution was prepared by adding 1,2 - diamino-2-
methylpropane (8.2 gm, 93 mmol, 2 equiv) to ethanol (150 ml) at room temperature and it was
cooled to - 10°C). The vessel was washed with dichloromethane -ethanol solution (7.5+7.5ml).
The temperature of reaction mixture was raised to room temperature. The organic layer was
concentrated at 35 to 40°C imder reduced pressure to get a thick oily mass. Dichloromethane
(300 ml) was added at room temperature under stirring. Deionized (DI) water (150 ml) was
added at room temperature under stirring. The reaction mixture was stirred at room temperature
for about 30 minutes and settled for about 30 minutes at room temperature. The organic layer
was separated. It was washed with 150 ml of saturated sodium bicarbonate solution. The layer
6
was settled for about 30 minutes and the organic layer was separated. The organic layer was
washed with 150 ml of DI water at room temperature. The layer was settled for about 30
minutes and the organic layer was separated. The organic layer was concentrated at 35 to 40°C
under reduced pressure. Hexane (150 ml) was added and the reaction mass was stirred at 35 to
40°C for about 30 minutes and cooled to room temperature. The solid was filtered and washed
with hexane (15 ml). The material obtained was dried at room temperature under reduced
pressure for 10-12 hrs till constant weight was obtained.
Yield: 16.8 gm (1.12 w/w), 92.0%
Mass 393, HPLC Purity 96.72%,
'HNMR (400 MHz, DMS0-fi?6): 5 0.93 (s, 6H), 1.10 - 1.05 (m, 2H), 1.89-1.64 (m, 21H), 2.03
- 2.01 (d,2H), 2.93 (d,2H).
Example 3: Preparation of cis-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methvl propyl)
amino] carbonyl] methvlj-T, 2\ 4'-trioxaspiro [4.5] decane
Step a : Preparation of (Is, 4s)-dispiro [cyciohexane-1,3'-[l,2,4] trioxolane-5', 2"-
tricyclo [3.3.1.1^'^] decaii]-4-yIacetyl ethyl carbonate
(Is, 4s)-Dispiro [cyclohexane-1, 3'-[l,2,4] trioxolane-5', 2"-tricyclo [3.3.1.1^-^]
decan]-4-ylacetic acid (1.5 gm, 4.65 mmol, 1 equiv) was taken in dichloromethane (15 ml) at
room temperature under dry nitrogen atmosphere. Tri ethylamine (0.75 gm, 7.44 mmol, 1.6
equiv) was added at room temperature. The reaction mixture was cooled to - 10°C. Ethyl
chloroformate (0.50 gm, 4.65 mmol, 1 equiv) was added slowly at - 10 to -5°C, under
stirring. The mixture was stirred for about 20 -30 minutes. The reaction mass was diluted
with dichloromethane (20 ml) and deionized water (15 ml) was added at room temperature
under stirring. The reaction mixture was stirred at room temperature for about 10 minutes and
settled for about 15 minutes, at room temperature. The organic layer was separated. It was
washed with 10 ml of 25% sodium chloride solution. The layer was settled for about 15
minutes and the organic layer was separated. It was concentrated at 25 to 30°C under reduced
pressure to obtain solid residue. It was further dried at 30-35 °C under reduced pressure for
about 3 h till constant weight was obtained.
Yield: 1.70 gm (1.13 w/w), 92.63%
Mass 394.45, Mass Purity: 99.58%
7
'HNMR (400 MHz, DMSO-de): 6 0.857 (s, 6H), 1.04 - 1.01 (m, 2H), 1.82-1.57 (m, 21H),
1.96 - 1.95 (d, 2H), 2.86 - 2.85 (d, 2H).
Step b: Preparation of cis-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyI propyl)
amino] carbonyl] methyl]-!', 2', 4'-trioxaspiro [4.5] decane
1,2 -Diamino-2-methylpropane (0.45 gm, 5.10 mmol, 2 equiv) was taken in ethanol
(10 ml) at room temperature under dry nitrogen atmosphere. The reaction mixture was cooled
to - 10°C. Mixed anhydride solution [this solution was prepared by adding (Is, 4s)-dispiro
[cyclohexane-1, 3'-[l,2,4] trioxolane-5', 2"-tricyclo [3.3.l.l'''^] decan]-4-ylacetyl ethyl
carbonate (1.0 gm, 2.53 mmol, 1 equiv) (step a) to dichloromethane (10 ml) at room
temperature] was added drop wise at -10 to -5°C, under stirring. The temperature of reaction
mixture was raised to room temperature. The organic layer was concentrated at 35 to 40°C
under reduced pressure to get a thick oily mass. Dichloromethane (20 ml) was added at room
temperature under stirring. Deionized water (10 ml) was added at room temperature under
stirring. The reaction mixture was stirred at room temperature for about 30 minutes and
settled for about 30 minutes at room temperature. The organic layer was separated. It was
washed with 10 ml of saturated sodium bicarbonate solution. The layer was settled for about
30 minutes and the organic layer was separated. The organic layer was washed with 5 ml of
DI water at room temperature. The layer was settled for about 30 minutes and the organic
layer was separated. The organic layer was concentrated at 35 to 40°C under reduced
pressure. Hexane (10 ml) was added and the reaction mass was stirred at 35 to 40°C for about
30 minutes and cooled to room temperature. The solid was filtered and washed with hexane
(1.0 ml). The material obtained was dried at room temperature under reduced pressure for
about 3 hrs till constant weight was obtained.
Yield: 0.9 gm (0.9 w/w), 90.44%
Mass 393, HPLC Purity: 98.83%,
'HNMR (400 MHz, DMSO-de): 5 0.855 (s, 6H), 1.03 - 1.00 (m, 2H), 1.82-1.57 (m, 21H),
1.96 - 1.94 (d, 2H), 2.86 - 2.85 (d, 2H).
Example 4: Preparation of c/5-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methvl propyl)
amino] carbonyl] methyl]-!'. 1\ 4'-trioxaspiro [4.5] decane maleate
To a solution of cw-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl propyl) amino]
carbonyl] methyl]-!', 2', 4'-trioxaspiro [4.5] decane (10 gm, 25.47 mmole, 1 equiv) (example 2
(a), 2 (b) or 3) in ethanol (25 ml) was added a solution of maleic acid (2.89 gm, 24.96 mmole,
8
0.98 equiv) in ethanol (15 ml) and the reaction mixture was stirred for about 1 h. To this clear
solution, n-hexane (120 ml) was added at room temperature in about 1 h and then reaction
mixture was stirred for about 4 to 5 h. It was then cooled to 5 to 10*^C and stirred for about
another 1 h and filtered at the same temperature. The cake was slurry washed with n-hexane
(10 ml) and dried under vacuum at 25-35*^0 for about 12 to 16 hrs.
Yield: 10.99 gm, 85.19%, mp: 149V (decomp), (M^+1) 393.5,
'HNMR (400 MHz, DMS0-d6): 8 1.05-1.11 (m, 2H), 1.16 (s,6H), 1.64-1.89 (m, 21H), 2.07
(d, 2H), 3.20 (d, 2H), 6.02 (d, 2H), 7.7 (bs, 2H), 8.07 (t, IH).
9

WE CLAIM:
1. A process for the preparation of cw-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl
propyl) amino] carbonyl] methylj-l', 2', 4'-trioxaspiro [4.5] decane, of Formula III
H V>(
H
Formula III
having no dimer impurity of Formula IV,
H O O H
Formula IV
wherein the process comprises,
(a) reacting the compoimd of Formula II
A V / o ^ ^ o
H V>(^
H
Formula II
in dichloromethane with an activating agent forming a mixed anhydride, and
(b) reacting the mixed anhydride in situ with ethanolic solution of 1,2-diamino-2-
methylpropane to give compound of Formula III.
10
2. A process for the preparation of m-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl
propyl) amino] carbonyl] methyl]-!', 2', 4'-trioxaspiro [4.5] decane, of Formula III
H ^ / ^ ^ \ ^NH,
H v>(
H
Formula III
having no dimer impurity of Formula IV,
H O O H
Formula IV
wherein the process comprises,
(a) reacting the compound of Formula II
A'V/O ^-^ o
H v>(
H
Formula II
in dichloromethane with an activating agent forming a mixed anhydride,
(b) isolating the mixed anhydride, and
(c) reacting the dichloromethane solution of mixed anhydride with ethanolic solution of
1,2-diamino-2-methylpropane, to give compound of Formula III.
3. The process of claim 1 or 2, wherein 1.8-3 mole equivalents of 1,2-diamino-2-
methylpropane are used in 20- 80 times w/v of solvent system of dichloromethane and
ethanol (in the ratio of 1:1 v/v).
4. The process of claim 1 or 2 wherein the activating agent is selected from methyl
chloroformate, ethyl chloroformate, propyl chloroformate, n-butyl chloroformate,
isobutyl chloroformate and pivaloyl chloride.
11
5. The process of claim 1 or 2 wherein the reaction of a compound of Formula II with an
activating agent and 1,2-diamino-2-methylpropane to give compound of Formula III
is carried out in the presence of an organic base.
6. The process of claim 5 wherein the organic base is trimethyl amine, triethyl amine,
isopropyl amine or mixture(s) thereof.
7. The process of claim 1 or 2 wherein cw-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-
methyl propyl) amino] carbonyl] methyl]-!', 2', 4'-trioxaspiro [4.5] decane of
Formula III has HPLC purity not less than 96%.
8. Use of cw-adamantane-2-spiro-3' -8' - [ [ [(2' -amino-2' -methyl propyl) amino] carbonyl]
methylj-l', 2', 4'-trioxaspiro [4.5] decane, of Formula III
H v>(
H
Formula III
having no dimer impurity of Formula IV,
H O O H
Formula IV
produced by the process of claim 1 or 2 in the preparation of compounds of Formula
I,
H ^ ,-X ^^^^
7<
H
Formula I
12
wherein X is an anion, for example, acetate, adipate, alginate, citrate, aspartate,
benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate,
digluconate, glycerophosphate, glycolate, malonate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate,
maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate,
pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene sulfonate or
undecanoate.
9. The use of claim 8 wherein c/5'-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl
propyl) amino] carbonyl] methylj-l', 2', 4'-trioxaspiro [4.5] decane of Formula III
has HPLC purity not less than 96%.
10. The use of claim 8 wherein the process for the preparation of compounds of Formula I
A V / ' O ^ ^ O . HX
H \ -K
H
Formula I
comprises reacting the compound of Formula III
H V><
H
Formula III
with an acid of Formula HX (wherein X is the same as defined above) to give
compounds of Formula I.
11. The process of claim 10 wherein the reaction of a compound of Formula III with an
acid of Formula HX to give a compound of Formula I is carried out in an alcoholic
solvent, hydrocarbon solvent or mixture(s) thereof
12. The process of claim 11 wherein the alcoholic solvent is methanol, ethanol,
isopropanol or mixture(s) thereof
13
13. The process of claim 11 wherein the hydrocarbon solvent is hexane, heptane or
mixture(s) thereof.
14. c/5'-Adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl propyl) amino] carbonyl]
methyl] - 1 ' , 2', 4' -trioxaspiro [4.5 ] decane, of Formula III
H \^H
Formula III
having no dimer impurity of Formula IV,
H O O H
Formula IV
produced by the process of claim 1.
15. c/5-Adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl propyl) amino] carbonyl]
methyl]-r, 2', 4'-trioxaspiro [4.5] decane, of Formula III
H V><
H
Formula III
having no dimer impurity of Formula IV,
H^V::/ '-' O >'•• \_J ^NhH NH^(\__/ "" O ^^^ ycTH O O H
Formula IV
produced by the process of claim 2.
14
Dated this the 3^^ day of November, 2011.
For Ranbaxy Laboratories Limited
L,j^'^—'
(Dr. Santanu De)
Associate Director - Intellectual Property
15