NOVEL SYNTHESIS AND CRYSTALLIZATION OF PIPERAZINE RING-CONTAINING COMPOUNDS

NOUVELLE SYNTHESE ET CRISTALLISATION DE COMPOSES CONTENANT DE LA PIPERAZINE

English Abstract

The present invention is directed to methods for the preparation of piperazine
ring-containing compounds, particularly mirtazapine. According to the present
invention, the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-
phenyl-piperazine is made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-
phenyl-piperazine with a base where the base is present in a ratio of up to
about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-
phenyl-piperazine. The mirtazapine intermediate 1-(3-carboxypyridly-2)-4-
methyl-2-phenyl-piperazine may be made by hydrolyzing 1-(3-cyanopyridyl-2)-4-
methyl-2-phenyl-piperazine with potassium hydroxide at a temperature of at
least about 130 ~C. The method of the present invention also includes reacting
2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2, 2'-iminodiethyl
chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine,
and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-phenyl-4-
methylpiperazine to form mirtazapine. The present invention also relates to
new processes for recrystallization of mirtazapine form crude mirtazapine.

French Abstract

L'invention concerne des procédés de préparation de composés contenant de la pipérazine, notamment de la mirtazapine. Selon l'invention, l'intermédiaire de mirtazapine 1-(3-carboxypyridyl-2)-4-méthyl-2-phényl-pipérazine est fabriqué par l'hydrolyse de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine avec une base, laquelle est présente selon un rapport pouvant atteindre environ 12 moles de la base par mole de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine. L'intermédiaire de mirtapazine de 1-(3-carboxypyridyl-2)-4-méthyl-2-phényl-pipérazine peut être fabriqué par hydrolyse de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine avec de l'hydroxyde de potassium, à une température d'au moins environ 130 ·C. Le procédé de l'invention consiste également à faire réagir du 2-amino-3-hydroxyméthyl pyridine avec du chlorure de N-méthyl-1-phényl-2, 2'-iminodiéthyle, de sorte que de la 1-(3-hydroxyméthylpyridyl-2)-4-méthyl-2-phényl pipérazine soit formée, et à ajouter de l'acide sulfurique à la 1-(3-hydroxyméthylpyridyl-2)-phényl-4-méthylpipérazine, de sorte que de la mirtazapine soit formée. L'invention porte également sur des nouveaux procédés de cristallisation de la mirtazapine, permettant la production de mirtazapine brute.

Claims

WE CLAIM:
1. A method for the preparation of mirtazapine, comprising the steps of:
(a) reacting a compound of the formula <IMG> with a compound of
the formula <IMG>
to form a compound of the formula <IMG>
(b) adding a ring closing reagent to the compound of the
formula <IMG> to form mirtazapine
15

wherein R1 is selected from the group consisting of hydroxymethyl,
chloromethyl,
bromomethyl and iodomethyl; R2 is amine; and R3 is selected from the group
consisting of
chloro, fluoro, bromo and iodo.
2. The method of claim 1, wherein R1 is hydroxymethyl, R2 is -NH2, and R3 is
chloro.
3. The method of claim 1, wherein said a ring closing reagent is selected from
the
group consisting of sulfuric acid, concentrated sulfuric acid, concentrated
hydrochloric acid,
trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorus
oxychloride,
phosphorus trioxide, phosphorus pentoxide, Lewis acids, aluminum chloride,
ferric chloride,
zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony
pentachloride and
zirconium tetrachloride.
4. The method of claim 2, wherein said ring closing reagent is sulfuric acid.
5. The method of claim 1 which further comprises the step of heating.
6. A method for the preparation of mirtazapine, comprising the steps of:
(a) reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-
2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-
phenyl-
piperazine, and
(b) adding a ring closing reagent to the 1-(3-hydroxymethylpyridyl-2)-4-
methyl-2-phenyl-piperazine to form mirtazapine.
7. The method of claim 6, wherein said a ring closing reagent is selected from
the
group consisting of sulfuric acid, concentrated sulfuric acid, concentrated
hydrochloric acid,
trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorus
oxychloride,
phosphorus trioxide, phosphorus pentoxide, Lewis acids, aluminum chloride,
ferric chloride,
16

zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony
pentachloride and
zirconium tetrachloride.
8. The method of claim 6 wherein the ring closing reagent is sulfuric acid.
9. The method of claim 6 further comprising the step of heating.
10. A process for making 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine
by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine comprising
the step of
reacting 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base wherein
the base is
present in a ratio of up to about 12 moles of the base per one mole of 1-(3-
cyanopyridyl-2)-4-
methyl-2-phenyl-piperazine.
11. The process of claim 10 wherein the ratio of the base to 1-(3-cyanopyridyl-
2)-
4-methyl-2-phenyl-piperazine is about 12 moles of base to about one mole of 1-
(3-
cyanopyridyl-2)-4-methyl-2-phenyl-piperazine to about 9 moles of base to about
one mole of
1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
12. The process of claim 10 wherein the base is potassium hydroxide or sodium
hydroxide
13. The process of claim 12 wherein the mixture of the 1-(3-cyanopyridyl-2)-4-
methyl-2-phenyl-piperazine and the base is heated to at least about
130°C.
14. The process of claim 13 wherein the mixture is heated to about
130°C to about
150°C.
15. The process of claim 12 wherein the hydrolysis is carried out in water and
an
aprotic polar solvent.
17

16. The process of claim 12 wherein the hydrolysis is carried out in a mixture
of
water and a solvent selected from the group consisting of methanol, ethanol,
propanol,
isopropanol, butanol, dimethylformamide, dimethylacetamide and
dimethylsulfoxide.
17. The process of claim 12 wherein the hydrolysis is carried out at a
pressure of
about 3 to about 4 atmospheres pressure.
18. The process of claim 12 wherein the hydrolysis is carried out at almost
neat
conditions.
19. A process for recrystallized mirtazapine from crude mirtazapine comprising
the
steps of:
(a) heating a mixture of crude mirtazapine and a solvent;
(b) cooling the mixture such that purified mirtazapine precipitatis; and
(c) isolating the recrystallized mirtazapine.
20. The process of claim 19 wherein the solvent is selected from the group
consisting of methanol, ethanol, isopropanol, acetone, and mixtures thereof.
21. The process of claim 20 further comprising the step of adding water to the
mixture of mirtazapine and solvent to facilitate precipitation of mirtazapine.
22. The process of claim 19 where in the solvent is selected from the group
consisting of toluene, hexane, and methylene chloride, and mixtures thereof.
23. The process of claim 20 wherein the solvent is ethanol.
24. The process of claim 19 wherein the recrystallized mirtazapine is a
mirtazapine
water adduct.
18

25. The product of the process claim 24.
26. Mirtazapine prepared according to the process of claim 1.
27. A pharmaceutical composition comprising a therapeutically effective amount
of
mirtazapine of claim 26, and a pharmaceutically acceptable carrier.
28. A method for the treatment of depression, comprising the step of
administering
to a human subject in need of such treatment the pharmaceutical composition of
claim 27.
19

Description

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NOVEL SYNTHESIS AND CRYSTALLIZATION OF PIPERAZINE
RING-CONTAINING COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application No.
60/130,047, filed April 19, 1999.
FIELD OF THE INVENTION
The present invention relates to synthetic organic chemistry, particularly, to
synthesis of piperazine ring-containing compounds, such as mirtazapine, and to
the
crystallization of mirtazapine from different solvents and solvent systems.
BACKGROUND OF THE INVENTION
Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino
[2,1-a]pyrido[2,3-c][2] benzazepine, having the formula I:
i
I \
N N
~N
CH3
is approved, under the trademark Remeron~, by the U.S. Food and Drug
Administration, for
the treatment of depression. Mirtazapine has a tetracyclic chemical structure
unrelated to
other classes of antidepressants such as selective serotonin reuptake
inhibitors, tricyclics or
monoamine oxidase inhibitors. Mirtazapine belongs to the piperazinoazepine
group of
compounds.
Mirtazapine may be made by methods described in U.S. Patent No. 4,062,848.
By a process of U.S. Patent No. 4,062,848 ("the '848 patent"), the mirtazapine
intermediate
1-(3-hydroxymethylpyridyl-2-4-methyl-2-phenyl-piperazine is made by a three
step process
starting with a 2,3-substituted pyridine derivative. Therefore, as shown in
Scheme 1, when
starting with 2-amino-3-cyano-pyridine, the process of the '848 patent
requires four synthetic
steps to make mirtazapine. It is desirable to have a process for making
mirtazapine that
requires fewer steps, and therefore requires less reagent, solvent and time.

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Scheme 1
CN CI ~ Step 1 ~ I CN ~ I Step 2
~ CH ----~ ~N ~N \
N- _NH2 2
CI EtOH
H3C~ ~CH2-CH2 N\
CH3
2-amino- N-methyl-I-phenyl- 1-(3-cyanomethylpyridyl-2)-
3-cyano-pyridine 2,2'-iminodiethyl chloride 4-methyl-2-phenyl-piperazine
COOH CH20H
Step 3 ~ ( ~ I Step 4
~N N \ LiAIH4 ~N N \ H2S0~
~N ~N
CH3 CH3 CH3
I-(3-carboxymethylpyridyl-2)- I-(3-hydroxymethylpyridyl-2)-
4-methyl-2-phenyl-piperazine 4-methyl-2-phenyl-piperazine Mirtazapine
2

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By the process of U.S. Patent No. 4,062,848 ("the 848 patent"), the
mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine
is made by
the hydrolysis of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-
piperazine under highly
basic conditions of 25 moles of potassium hydroxide (KOH) per mole of nitrile,
at high
temperature and for long reaction times of 24 hours. These harsh reaction
conditions
necessitate a great effort in purifying the resulting product as well as
creating environmental
waste disposal issues associated with neutralizing and disposing of large
volumes of
concentrated basic solutions. The highly basic conditions and long reaction
times make the
procedure of the '848 patent very costly, especially in terms of reactor time.
According to the methods of U.S. Patent No. 4,062,848, crude mirtazapine is
recrystallized only in ether and petrol ether 40-60. The solvents ether and
petrol ether 40-60
are both very difficult to handle in large scale production.
SUMMARY OF THE INVENTION
The present invention is directed to a method for the preparation of
R~
mirtazapine, comprising the steps of: reacting a compound of the formula N R2
R3 w
CH2
R3
,N
with a compound of the formula H3C ~ to form a compound of the formula
R'
N N _
~N
CH3 , and

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R~
/ /
N N _
~N
adding a ring closing reagent to the compound of the formula ~H3 to form
mirtazapine, wherein R' is selected from the group consisting of
hydroxymethyl,
chloromethyl, bromomethyl and iodomethyl; Rz is amine; and R3 is selected from
the group
consisting of chloro, fluoro, bromo and iodo.
In a preferred embodiment of the present invention is directed to a method for
the preparation of mirtazapine, comprising the steps of reacting 2-amino-3-
hydroxymethyl
pyridine with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-
hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid
to the 1-(3-
hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine.
Further, it has now been discovered that the mirtazapine intermediate 1-(3-
carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made by hydrolysis of
the nitrile 1-
(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine using new more favorable
reaction
conditions. The new reaction conditions of the present invention include a low
mole to mole
ratio of potassium hydroxide to nitrite and shorter reaction times.
The present invention relates to a improved process for making 1-(3-
carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing 1-(3-
cyanopyridyl-2)-4-
methyl-2-phenyl-piperazine comprising the step of reacting 1-(3-cyanopyridyl-
2)-4-methyl-2-
phenyl-piperazine with a base wherein the base is present in a ratio of up to
about 12 moles of
the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
In a preferred embodiment of the present invention, the ratio of the base to 1-
(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12 moles of base to
about one
mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine to about 9 moles of
base to about
one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
In another preferred embodiment of the present invention, the base is
potassium hydroxide or sodium hydroxide.
4

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In another embodiment of the present invention, the mixture of the 1-(3-
cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at
least about 130° C.
In another embodiment of the present invention, the hydrolysis of 1-(3-
cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is carried out in a mixture water
and a solvent
selected from the group consisting of methanol, ethanol, propanol,
isopropanol, butanol,
dimethylformamide, dimethylacetamide and dimethylsulfoxide.
The present invention also relates to improved processes for making
mirtazapine from crude mirtazapine comprising the steps of (a) heating a
mixture of crude
mirtazapine and solvent; and (b) isolating mirtazapine.
In a preferred embodiment of the present invention, water is added to the
heated mixture of mirtazapine and solvent to facilitate precipitation of
mirtazapine.
In an additional embodiment of the present invention, preferred solvents are
methanol, ethanol, isopropanol, acetone, toluene, and hexane and mixtures
thereof.
In an additional embodiment of the present invention, preferred solvents are
toluene, hexane, and methylene chloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for preparing piperazine ring-
containing compounds, such as mirtazapine, as described in Scheme 2 below. The
process of
the present invention is advantageous over prior art processes due to, inter
alia, the higher
yield, smaller number of steps in relation to the alternative methods, and
minimized raw
material costs.
Scheme 2
/ R~ / i
/ R~ R3 ~ ~ ~ ~ ~ wN~ \
+ N N N
CH2
N R I R3 ~N ~N
H3C~N~---~ CH3 CH3
II III IV
Mirtazapine

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More particularly, the present invention relates to the process of making
mirtazapine from compounds of the formulae II, III and IV. In the process of
the present
invention the compound of formula II in Scheme 2 above, wherein R' denotes
hydroxymethyl, chloromethyl, bromomethyl or iodomethyl, and RZ denotes amine,
preferably
-NHz, is reacted with the compound of formula III in Scheme 2 above, wherein
R3 denotes
chloro, fluoro, bromo or iodo, to form the compound of formula IV wherein R'
is defined as
above.
In the process of the present invention, the compound of formula II is
dissolved in a solvent such as methylene chloride. The compound of formula III
is added to
the solvent mixture and the resulting mixture is heated. Preferably the
reaction mixture is
heated to the reflux temperature of the solvent. The mixture is heated to form
the compound
of formula IV. Mirtazapine is then prepared by ring closure of the compound of
formula IV.
Ring closure of the compound of formula IV may be performed using a ring-
closing reagent.
Suitable ring closing reagents are dehydrating or dehydrohalogenating agents.
Dehydrating
or dehydrohalogenating agents that may be added to the reaction mixture for
this purpose
include acids, such as sulfuric acid, concentrated sulfuric acid, concentrated
hydrochloric
acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA),
phosphorus
oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis acids, such
as aluminum
chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride,
boron trifluoride,
antimony pentachloride and zirconium tetrachloride.
Dehydrating agents that are particularly preferred are sulfuric acid and
phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated
sulfuric acid
most preferred. A particularly preferred dehydrohalogenating agent is aluminum
chloride.
In a preferred embodiment of the present invention the compounds of the
formulae II, III and IV are compounds of the formulae II', III' and IV'
respectively as shown
in Scheme 3 below. In an embodiment of the present invention, 2-amino-3-
hydroxymethyl
pyridine is reacted with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form
1-(3-
hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine. In the present
invention, 2-amino-
3-hydroxymethyl pyridine (II') is added to a solvent. Suitable solvents
include 1,2-
dichloroethane, methylene chloride, dimethylformamide, dimethylacetamide and
dimethylsulfoxide. N-Methyl-1-phenyl-2,2'-imidodiethyl-chloride (III') is
added to the
6

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solvent mixture and the resulting mixture is heated. Preferably the reaction
mixture is heated
to the reflux temperature of the solvent. The mixture is heated until 1-(3-
hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is formed and the
reaction is
complete. A suitable time is about six to about 24 hours. The 1-(3-
hydroxymethylpyridyl-2)-
4-methyl-2-phenyl-piperazine is then converted to mirtazapine by ring closure.
The ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-
piperazine is performed under strongly dehydrating (R'= OH) conditions,
preferably at an
elevated temperature. Suitable dehydrating agents, include acids, such as
sulfuric acid,
concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid,
polyphosphoric acid
(PPA), phosphorus oxychloride, phosphorus trioxide and phosphorus pentoxide.
Dehydrating
agents that are particularly preferred are sulfuric acid and phosphorus
derivatives, such as
PPA and phosphorus oxychloride. Concentrated sulfuric acid is most preferred.
7

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Scheme 3
/ \ ~ _
CH20H CI ~ wN~
+ ~ ~ N
\N- _NH CH2
/CI ~N
H3C~N~ CH3
I I' I I I' IV'
2-amino- N-methyl-1-phenyl- 1-(3-hydroxymethylpyridyl-2)- Mirtazapine
3-hydroxymethyl 2,2'-iminodiethyl chloride 4-methyl-2-phenyl-piperazine
pyridine
The present invention also provides new processes for making the mirtazapine
intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the
nitrite 1-(3-
cyanopyridyl-2)-4-methyl-2-phenyl-piperazine where the nitrite is (I)
hydrolyzed by base
using a new low mole to mole ratio of base to the nitrite 1-(3-cyanopyridyl-2)-
4-methyl-2-
phenyl-piperazine and (ii) hydrolyzed using short reaction times.
Where the present invention provides improved methods for making the
mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine,
the nitrite 1-
(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is dissolved in a mixture of
water and
organic solvent. Preferred organic solvents include polar aprotic solvents and
alcohols. Polar
aprotic organic solvents such as dimethylformamide, dimethylacetamide and
dimethylsulfoxide and the like are preferred. Preferred alcohols are methanol,
ethanol,
propanol, isopropanol, butanol and the like. A suitable amount of base, such
as potassium
hydroxide or sodium hydroxide, is added to the reaction mixture. An amount of
base, such as
potassium hydroxide or sodium hydroxide, of up to about 12 moles of base per
mole of nitrite
(for example 12:1 KOH:nitrile) is preferred. Amounts of base, such as
potassium hydroxide,
in the ratio of about 9 moles of potassium hydroxide per one mole of nitrite
(9:1
KOH:nitrile), to about 12 moles of potassium hydroxide per mole of nitrite
(12:1
KOH:nitrile) are preferred.
In the present invention, the mixture of the nitrite 1-(3-cyanopyridyl-2)-4-
methyl-2-phenyl-piperazine, solvent and base is heated to at least about
130°C. Reaction

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temperatures of about 130°C to about 150° are preferred. In an
embodiment of the present
invention, the reaction may be conducted under pressure to facilitate the
attainment of high
temperatures. A pressure of at least about 3 atmospheres is preferred.
Pressures of at least
about 3 atmospheres to about 4 atmospheres are more preferred. The reaction
mixture is
heated until the reaction is complete. The completion of the reaction may be
monitored by
HPLC. The amount of time needed for the completion of the hydrolysis of the
nitrite vaxies
with the temperature of the reaction. Higher reaction temperatures generally
require shorter
reaction times, while lower reaction temperatures generally requires longer
reaction times.
While not limiting the reaction time of the present invention, preferred
reaction times of the
present invention may be from about 2 hours to about 8 hours. Upon completion
of the
reaction, the pH of the reaction mixture is lowered, preferably to a pH of
about 6 to about 7.
Preferably the pH is lowered with hydrochloric acid. The mirtazapine
intermediate,l-(3-
cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated following washing and
filtration of
the reaction mixture.
In an additional embodiment of the present invention, the reaction mixture of
the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, and potassium
hydroxide, is
heated while using a minimum amount of water, such as about 0.25-1 mL of water
per gram
of KOH, and small amounts of an aprotic solvent such as dimethylformamide,
dimethylacetamide and dimethylsulfoxide, such as about 0.1 to 0.5 grams of
aprotic solvent
per gram of nitrite, under very concentrated conditions or almost neat
conditions at
atmospheric pressure. The mirtazapine intermediate,l-(3-cyanopyridyl-2)-4-
methyl-2-
phenyl-piperazine is isolated following washing and filtration of the reaction
mixture.
The new processes of the present invention for making the mirtazapine
intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the
nitrite 1-(3-
cyanopyridyl-2)-4-methyl-2-phenyl-piperazine significantly reduce the quantity
of potassium
hydroxide used, from 25 moles of potassium hydroxide per mole of the nitrite
as in the '848
patent, to about 12 moles or less of potassium hydroxide to one mole of the
nitrite. The
reduction in the amount of base needed considerably simplifies the work-up of
the reaction
and minimizes environmental problems.
The present invention also provides new methods for making pure mirtazapine
by purifying crude mirtazapine by recrystallization. Upon the ring closure of
9

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1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine,
the crude
product, mirtazapine, is purified by recrystallization.
It has been discovered that common solvents such as toluene or methylene
chloride and solvent systems such as alcohol-water can be used in the
recrystallization of
crude mirtazapine. According to the present invention, crude mirtazapine is
suspended in a
suitable solvent. Preferred solvents include methanol, ethanol, isopropanol,
and acetone and
mixtures thereof, or mixtures of one or more of those solvents with water.
Additional
preferred solvents also include toluene, hexane, and methylene chloride.
Solvent mixtures of
water and ethanol are more preferred. Solvent mixtures of ratios of about 1:1
to about 1:4
ethanol:water are preferred.
In the present invention, the suspension of crude mirtazapine and solvent is
heated to a suitable temperature. Suitable temperatures include, for example,
the reflux
temperature of the solvent system being used in any particular embodiment of
the present
invention. For example, in an embodiment of the present invention where
toluene is the
solvent, a temperature of about 110°C is suitable. Purified mirtazapine
precipitates upon
cooling of the reaction mixture. Filtration and drying of the resulting
precipitate yields
purified, recrystallized mirtazapine.
In a further example, crude mirtazapine is suspended in a solvent such as
ethanol, and the mixture is heated to reflux. Water is then added dropwise and
the solution is
cooled to facilitate precipitation of mirtazapine. The precipitate is purified
by filtration,
washing and drying to yield purified mirtazapine. The crystallized mirtazapine
may be a
water adduct thereby containing up to 3 % water by weight (3% w/w).
The solvents and solvent systems of the present invention are suitable for
large
scale reactions, and are more suitable for laxge scale reactions than ether or
petrol ether 40-60.
Additionally, the crystallization yield can be substantially improved when
using the solvent
system of the present invention.
Mirtazapine and mirtazapine intermediates, 1-(3-cyanopyridyl-2)-4-methyl-2-
phenyl-piperazine and 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine each
contain an
asymmetric carbon atom, as a result of which separate optical isomers may be
prepared in
addition to a racemic mixtures. Processes of the present invention include
these optical

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isomers just as the racemic mixtures are included in the invention.
In accordance with the present invention, mirtazapine produced by the process
of the present invention may be prepared as pharmaceutical compositions that
are particularly
useful for the treatment of depression. Such compositions comprise a
therapeutically
effective amount of mirtazapine with pharmaceutically acceptable carriers
and/or excipients
known to one of skill in the art.
EXAMPLES
The following examples are given for the purpose of illustrating the present
invention and shall not be construed as being limitations on the scope or
spirit of the
invention.
EXAMPLE 1
Preparation of 1-(3-Hydroxymethylpyridyl-2)-4-Methyl-2-Phenyl-Piperazine
In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser
and a thermometer 1 g (0.008 mole) of 2-amino-3-hydroxymethyl pyridine and 20
mL of 1,2-
dichloroethane were charged. The mixing is started and to the suspension 2.8 g
(0.012 mole)
of N-methyl-1-phenyl-2,2'-iminodiethyl-chloride are added. The reaction
mixture is heated to
reflux (~80° C) and maintained at this temperature for six hours.
After six hours the reaction mixture is cooled and the solvent (1,2-
dichloroethane) is removed by dry distillation. A yellowish powder is obtained
which
contains 1.8 g 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine
(yield 80%).
This powder can be used without additional purification for the preparation of
mirtazapine.
EXAMPLE 2
Preparation of Mirtazapine
In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser
and a thermometer 1.8 g of 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-
piperazine are
added to -~-5 mL of concentrated sulfuric acid that was previously cooled to
10°C. The
obtained solution is mixed at room temperature for 4 hours, then heated for
one hour to about
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50° to 60° C. After cooling, the reaction mass is added to 25 g
of ice under mixing and
neutralized with a concentrated ammonia solution or sodium hydroxide. The
formed
precipitate is separated by filtration. The mother liquor is evaporated to
dryness under
vacuum. Both the formed precipitate and the residue from the mother liquor are
each
suspended in ~ 20 mL of isopropanol. The combined isopropanol extracts are
evaporated to
dryness. An oil is obtained which contains 1.35 g of mirtazapine (yield 80%).
Example 3
Preparation of Mirtazapine
1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine (1.8 g) is added
to ~5 mL of concentrated sulfuric acid. The resulting solution is mixed at
35° C for 6 hours.
After cooling, the reaction mixture is added to 25 g of ice under mixing and
basified with a
concentrated ammonia solution or sodium hydroxide solution to pH = 10. The
separated
precipitate is extracted into methylene chloride and the extract is evaporated
to dryness; 1.6 g
of Mirtazapine is obtained (yield 95%).
Example 4
Preparation of 1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine
1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) is dissolved in 340
mL of ethanol and 34 mL of water. Potassium hydroxide flakes, 85% (113 g), are
added and
the reaction mixture is heated in an autoclave to 140° C. The pressure
increases to 3-4
atmospheres and the reaction mixture is maintained under pressure with mixing
for 5 hours.
After 5 hours, the reaction mixture is cooled, the ethanol is removed from the
mixture by
vacuum distillation, fresh water and toluene are added and the 2 phases are
separated. The
water solution is neutralized with hydrochloric acid (HCl) to pH = 6.5-7. At
pH = 6.5-7 the
water is evaporated and toluene is added. The inorganic salts are filtered and
the toluene
solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-2-)-4-
methyl- 2-
phenyl-piperazine (yield: 90%).
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Example 5
Preparation of 1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine
Potassium hydroxide (150 g of KOH flakes, 85%) and 75 mL of water and 6.5
g of DMSO are added to 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54
g) and the
reaction mixture is heated to 145-150° C and mixed for 8 hours. After 8
hours, the inorganic
phase containing water and potassium hydroxide (KOH) is separated and the
organic phase,
containing mainly a product oil, is cooled. Fresh water and toluene are added
and the two
phases are separated. The aqueous solution is neutralized with HCl to pH = 6.5-
7. At pH =
6.5-7, the water is evaporated and toluene is added. The inorganic salts are
filtered and the
toluene solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-
2-)-4-methyl-
2-phenyl-piperazine (yield: 90%).
Examine 6
Recrystallization of Mirtazapine
Mirtazapine (20 g), obtained as in Examples 2 and 3, is suspended in 20 mL of
ethanol and heated to reflux. At reflux, 40 mL of water is added dropwise to
the solution
over one hour followed by cooling to 10° C. The resulting filter cake
is washed with a
solution of water:ethanol (2:1) and dried at 60° C under a vacuum.
Crystallized mirtazapine,
18 g, is obtained in 90% yield.
Table 1 sets forth a summary of additional experiments generally following
procedures described above wherein the Yield % is the percent yield of
mirtazapine crystals
from crude mirtazapine and the Purity % is the percent purity as compared to a
mirtazapine
standard.
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Table 1. Purification of Crude pine by allization
Mirtaza Recryst
Solvent systemRatio of solventsConditionsYield'
ml:ml/g
hexane 10 reflux 55
toluene 3 reflux 32
toluene 2 reflux 53
acetone/water 6:25 25 C 65
ethanol/water 7:10 reflux 67
methanol/water2.25:1.5 reflux 67
ethanol/water 1.5:2 reflux 72
isopropyl/water1.65:2 reflux 60
acetone-water 3:2 reflux 53
ethanol/water 1:1.3 reflux 70
ethanol/water 1.3:1.75 reflux 90.3
ethanol/water 1:4 reflux 100
ethanol/water 1.1:1.2 reflux 87.8
ethanol/water 0.8:0.9 reflux 90
ethanol/water 0.8:1 reflux 57
ethanol/water 0.6:0.7 reflux 89.1
ethanol/water 0.35:0.7 reflux 91.5
ethanol/water 0.6:0.69 reflux 87
ethanol/water 2:2.8 reflux 95.6
' g mirtazapine crystals 100 %/g mirtazapine crude 100
Although certain presently preferred embodiments of the invention have been
described herein, it will be apparent to those skilled in the art to which the
invention pertains
that variations and modifications of the described embodiments may be made
without
departing from the spirit and scope of the invention. Accordingly, it is
intended that the
invention be limited only to the extent required by the appended claims and
the applicable
rule of law.
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