FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10]
"NOVEL SYNTHESIS OF PIPERAZINE RING"
TEVA PHARMACEUTICAL INDUSTRIES LTD., having a place of business at 5 Basel Street, P O Box 3190, Petah Tiqua 49131, Israel,
The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:-

NOVEL SYNTHESIS OF PIPERAZINE RING
5 RELATED APPLICATION
This application claims the benefit under 35 U.S.C. § 119(e) of U.S Provisional application, Serial No. 60/130,048, filed April 19, 1999.
FIELD OF THE INVENTION
10 The present invention relates to methods for the synthesis of pipera/.in.1
rings, particularly for the preparation of heterocyclic compounds useful as intermedi.au: i the synthesis of piperazinoazepines such as the antidepressant mirtazapine.
BACKGROUND OF THE INVENTION
15 Mirtazapine, also known as 1,2,3,4, lO,14b-hexahydro-2-methylpyra/irK
[2,l-a]pyrido[2,3-c] benzazepine, is an antidepressant suitable for oral administration, has a tetracyclic chemical structure unrelated to other classes of antidepressants sut 1 u> selective serotonin reuptake inhibitors (SSRls), tricyclics or monoamine oxidase inhibitors. Mirtazapine belongs to the piperazinoazepine group of compounds, and has r
20 following structural formula.

Known methods for the preparation of piperazine ring derivatives have 1< 25 yields (9-30%), expensive reagents, and many reaction steps (Roderick, W.R. et al.
Med. Chem 9, 1966, 181-185). It is desirable to have methods for preparing piperazne ring derivatives with fewer steps, high yields and inexpensive raw materials.

SUMMARY OF THE INVENTION
The present invention relates to a novel process for preparing a compouru of the formula I:

5
wherein
R' denotes substituted or unsubstituted alkyl, aryl, arylalkoxy, tosyl, formyl, benzoj 1
acetyl or amine; R2 denotes substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy ,)
arylalkoxy; and R3 denotes substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy 01
10 arylalkoxy; by reacting a compound of the formula

wherein R2 and R3 are as defined above and R4 and R5 are independently selected from tit.
15 group consisting of fluoro, chloro, bromo and iodo,
with a compound of the formula H2N-R', wherein R1 is as defined above. Preferably the reaction is performed in the presence of a solvent. Polar aprotic sohenb such as, dimethyl formamide, dimethylacetamide and dimethylsulfoxide are preferred
20 DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a new process for preparing piperazint; nr.s. ■ suitable for use in the synthesis of the antidepressant mirtazapine and other tetracyclic compounds such as those disclosed in U.S. Patent No. 4,062,848 to van der Burg, tht contents of which are incorporated herein by reference.
2

The process of the present invention comprises the steps of reacting ; compound of formula II:

5 wherein
R4 and R5 are independently any of the of radicals selected from the group that consbU
fluoro, chloro, bromo and iodo; and R2 and R3 are as defined above;
with a compound of the formula H2N-R', wherein R1 is as defined above. Preferabl -. ?
denotes aryl, acetyl, formyl, benzoyl, amine, or tosyl. Most preferably, R1 is tosyl In
10 order to remove any doubt, the tosyl radical is defined as the group of formula VI:

wherein Me represents a methyl group. Preferably R2 denotes methyl, R3 denotes phen> I
15 R4 denotes chloro, and R5 denotes chloro.
Preferably, the compounds of formulae I and II are compounds of fonnuu IV and V accordingly:
3

In a preferred embodiment, the present invention relates to a process K preparing a compound of formula XI:

10

wherein Ph represents a phenyl group, which comprises reacting a compound of fcrruj XII:

CI
J
with a compound of formula XIII:


Preferably this reaction takes place in the presence of a strong base such as sodium
hydroxide (NaOH), sodium hydride (NaH), potassium hydroxide (KOH), potassium
hydride (KH), sodium methoxide (NaOMe) and sodium amide (NaNH2). Sodium
hydroxide and sodium hydride are preferred.
5 Preferred solvents for the above reaction are any one or more of the
solvents selected from the group that consisting of dimethyl formamide (DMF), di'neT. v I
acetamide (DMAC), dimethyl sulfoxide (DMSO), xylene, benzene, ethylbenzene
acetonitrile, toluene and ethers with high boiling points such as ethyleneglycol dinet:p I
ether, diethyleneglycol dimethyl ether, and propyleneglycol dimethyl ether.
10 The compound of formula XI may be further hydrolized to give th>:
compound of formula XIV:
Me—N NH
M
Ph XIV
The compound of formula XIV is known as 4-mcthyl-2-phenylpiperazinc. Compounu ; »l
15 formula XI may be hydrolyzed by reacting a compound of the formula XI with acid to
give compounds of the formula XIV. Preferred acids for the reaction are strong acids u ;h
as sulfuric acid (H2S04), hydrochloric acid (HCl), phosphoric acid (H3P04) and p-tolut n ■
sulfonic acid. A more preferred acid is sulfuric acid with a concentration of about 98° ■
Preferably the reaction is carried out in aqueous solution.
20 The compound of formula XIV may be used in the preparation of the
mirtazapine (1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1 -a]pyrido[2,3-c] [2]
benzazepine), as shown in Schemes 1 and 2 below.
Scheme 1
5



CX, +
3-cyano-2-(4-methyl-2-phenyl -1-piperazynyl) pyridine
4-methyl-
2-phenyI peperazine
2-chloro-3-cyano-pyridine
As shown in Scheme 1, the compound 3-cyano-2-(4-methyl-2-phenyl-) -
5 piperazynyl) pyridine may be prepared starting from 2-chloro-3-cyano-pyridine and c-
methyl-2-phenyl-piperazine.
Starting from 3-cyano-2-(4-methyl-2~phenyl-l-piperazynyl)pyridine. mirtazapine can be prepared by two routes, which are further presented in Scheme 2:
10
6

10


In accordance with the present invention, mirtazapine produced by the process of the present invention may be prepared as pharmaceutical compositions that n particularly useful for the treatment of depression. Such compositions comprise mirtazapine with pharmaceutically acceptable carriers and/or excipients known to one . t skill in the art.

5

EXAMPLES
The following examples are given for the purpose of illustrating d c p \ -e n invention and shall not be construed as being limitations on the scope or spirit of the invention.
EXAMPLE 1


A suspension of sodium hydride (60%, 1.1 g) in DMF (20 mL) was prepared. p-Toluenesulfonamide (2.2 g) was dissolved in DMF (10 mL) and added continuously to the sodium hydride suspension. After mixing at room temperatuie tht. suspension was heated to 60-70°C.
15 After that, the solution of beta-chloro-N-methyl-N-chloroethyl
phenylethylamine (3 g) in DMF (10 mL) was added dropwise and mixed overnight I h reaction mixture was poured into a mixture of water (21 g) and ice (40 g).
After 4 hours the precipitate was filtered, washed with water (2 x V) ml and dried in an oven to give 3.3 g of the product.
20

EXAMPLE 2 Preparation of 4-merhyl-2-phenyl piperazine
/ \ /==\ H2S04 / Me—N N—S02—(v A—Me *- Me—N NH
Ph I'h
5
Tosyl piperazine (1.2 g) was dissolved in water (lg) and H2S04 (98%. ;
mL) while heating to 110°C. After 20 minutes at 110-120°C the reaction mixture wa ,
poured into water (10 mL) and ice (20 g).
The solution was alkalized to pH 13 with NaOH (47%) and the proiiue \ a >
10 extracted into ether. After phase separation the organic phase was evaporated to dr> nr*- >
to give the 4-methyl-2-phenyl piperazine in 75% yield.
Although certain presently preferred embodiments of the invention na\ .•
been described herein, it will be apparent to those skilled in the art to which the ir,\emi< n
15 pertains that variations and modifications of the described embodiment may be made
without departing from the spirit and scope of the invention. Accordingly, it is intends that the invention be limited only to the extent required by the appended claims and ih-.-applicable rules of law.
9

WE CLAIM:
1. A method for preparing a compound of the formula

wherein R' denotes substituted or unsubstituted alkyl, aryl, arvlalkoxy, tosyl. benzov! formyl, acetyl or amine; R2 denotes substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy or arylalkoxy; and R3 denotes substituted or unsubstituted alkyl, alkoxy, aryl. aryloxy or arylalkoxy,
comprising the step of reacting a compound of the formula


wherein R2 and R3 are as defined above and R4 and R5 are independently selected from in
15 group consisting of fluoro, chloro, bromo and iodo,
with a compound of the formula H2N-R', wherein R1 is as defined above.
2. The method of claim 1, wherein R1 is selected from the group consisting of ur\ acetyl, formyl, benzoyl, amine and tosyl.
20
3. The method of claim 2, wherein R1 is tosyl.
4. The method of claim 1, wherein R2 is methyl.
10

5. The method of claim 1, wherein R3 is phenyl.
6. The method of claim 1, wherein R4 is chloro.
5 7. The method of claim 1, wherein R5 is chloro.
8. The method of claim 1, wherein the reaction is performed in a solvent seleco
from the group consisting of DMF, DMAC, ethers, ethyleneglycol dimethyl ether
diethyleneglycol dimethyl ether, propyleneglycol dimethyl ether, DMSO, xylene, benzei e.
10 ethylbenzene, acetonitrile and toluene.
9. The method of claim 8, wherein said solvent is DMF.
10. The method of claim 1, further comprising the step of adding a strong fi.ise
15
11. The method of claim 10, wherein said strong base is selected from the group
consisting of sodium hydroxide, sodium hydride, potassium hydroxide, potassium hydn ie.
sodium methoxide and sodium amide.
20 12. The method of claim 11, wherein the base is sodium hydroxide.
13. The method of claim 11, wherein the base is sodium hydride.
14. The method of claim 1, further comprising the step of removing R' by
25 hydrolysis.
15. The method of claim 14, wherein R1 is removed by hydrolysis using a strong
acid.
30 16. The method of claim 15, wherein the acid is selected from the group consist ni:
11

of sulfuric acid, hydrochloric acid, phosphoric acid and p-toluene sulfonic acid.
17. The method of claim 16, wherein the acid is sulfuric acid.
5 18. The method of claim 17 wherein the sulfuric acid has a concentration v ;