FORM 2
THE PATENTS ACT 1970 [39 OF 1970]
&
THE PATENTS RULES, 2003 COMPLETE SPECIFICATION.
[See Section 10; rule 13]
"A METHOD FOR PREPARING A PIPERAZINE COMPOUND"
TEVA PHARMACEUTICAL INDUSTRIES LTD., of 5 Basel Street, P.O. Box 3190, Petah Tiqva 49131, Israel,
The following specification particularly describes the invention and the manner in which it is to be performed:


NOVEL SYNTHESIS OF PIPERAZINE RING
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
The present invention relates to methods for the synthesis of piperazine rings, particularly for the preparation of heterocyclic compounds useful as intermediates in the synthesis of piperazinoazepines such as the antidepressant mirtazapine.
BACKGROUND OF THE INVENTION
Mirtazapine, also known as l?2,3,4,10,14b-hexahydro-2-methylpyrazine [2,l-a]pyrido[2,3-c] benzazepine, is an antidepressant suitable for oral administration. It has a tetracyclic chemical structure unrelated to other classes of antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclics or monoamine oxidase inhibitors. Mirtazapine belongs to the piperazinoazepine group of compounds, and has the following structural formula.

Known methods for the preparation of piperazine ring derivatives have low yields (9-30%), expensive reagents, and many reaction steps (Roderick, W.R. et al., J. Med. Chem 9, 1966, 181-185). It is desirable to have methods for preparing piperazine 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 compound of the formula I:

wherein

R1 denotes substituted or unsubstituted alkyl, aryl, arylalkoxy, tosyl, formyl, benzoyl, 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; by reacting a compound of the formula
R4
R2—N R5
wherein R2 and R3 are as defined above and R4 and R5 are independently selected from the group consisting of fluoro, chloro, bromo and iodo,
with a compound of the formula H2N-R1, wherein R1 is as defined above. Preferably the reaction is performed in the presence of a solvent. Polar aprotic solvents such as, dimethyl formamide, dimethylacetamide and dimethylsulfoxide are preferred.
DETAILED DESCRIPTION OF THF. INVENTION
The present invention provides a new process for preparing piperazine rings 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, the contents of which are incorporated herein by reference.


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


R2—N


wherein
R4 and R5 are independently any of the of radicals selected from the group that consists of
fluoro, chloro, bromo and iodo; and R2 and R3 are as defined above;
with 2 ££>mpouDd of the Joranula H7N-R1, wberein R1 isas defined above. Preferably; Rl
denotes aryl, acetyl, formyl, benzoyl, amine, or tosyl. Most preferably, R1 is tosyl. In
order to remove any doubt, the tosyl radical is defined as the group of formula VI:

wherein Me represents a methyl group. Preferably R? denotes methyl, R3 denotes phenyl, R4 denotes chloro, and R5 denotes chloro.
Preferably, the compounds of formulae I and II are compounds of formulae IV and V accordingly:

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

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

Cl
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-Preferred solvents for the above reaction are any one or more of the solvents selected from the group that consisting of dimethyl formamide (DMF), dimethyl acetamide (DMAC), dimethyl sulfoxide (DMSO), xylene, benzene, ethylbenzene, acetonitrile, toluene and ethers with high boiling points such as ethyleneglycol dimethyl ether, diethyl eneglycol dimethyl ether, and propy I eneglycol dimethyl ether.
The compound of formula XI may be further hydrolized to give the compound of formula XIV:

The compound of formula XIV is known as 4-methyl-2-phenylpiperazine. Compounds of 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 such as sulfiiric acid (H2S04), hydrochloric acid (HC1), phosphoric acid (H3PO4) and p-toluene sulfonic acid. A more preferred acid is suliuric acid with a concentration of about 98%. Preferably the reaction is carried out in aqueous solution.
The compound of formula XIV may be used in the preparation of the mirtazapine(l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine), as shown in Schemes 1 and 2 below.
Scheme 1


As shown in Scheme 1, the compound 3-cyano-2-(4-meihyl-2-phenyl-l-piperazynyl) pyridine may be prepared starting from 2-chJoro-3-cyano-pyridine and 4-methyl-2-phenyl-piperazine.
Starting from 3-cyano-2-(4-methyI-2-phenyl-l-piperazynyl)pyridine, mirtazapine can be prepared by two routes, which are further presented in Scheme 2:



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 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

A suspension of sodium hydride (60%, 1.1 g) in DMF (20 mL) was prepared. p-ToIuenesuIfonamide (2.2 g) was dissolved in DMF (10 mL) and added continuously to the sodium hydride suspension. After mixing at room temperature the suspension was heated to 60-70°C.
After that, the solution of beta-chloro-N-methyl-N-chloroethyl
phenylethylamine (3 g) in DMF (10 mL) was added dropwise and mixed overnight. The 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 30 mL) and dried in an oven to give 3.3 g of the product.

EXAMPLE 2 Preparation of 4-methyl-2-phenvI piperazine

Tosyl piperazine (1.2 g) was dissolved In water (Ig) and H2S04 (98%, 3 mL) while heating to 110°C. After 20 minutes at 110-120°C the reaction mixture was poured into water (10 mL) and ice (20 g).
The solution was alkalized to pH 13 with NaOH (47%) and the product was extracted into ether. After phase separation the organic phase was evaporated to dryness to give the 4-methyI-2-phenyI piperazine in 75% yield.
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 embodiment 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 rules of law.

WE CLAIM:
1. A method for preparing a piperazine compound, comprising
(a) reacting a compound of the formula
wherein R2 denotes alkyl, alkoxy, aryl, aryloxy, or arylalkoxy, R3 denotes alkoxy, aryl, aryloxy^ or arylalkoxy, and R4 and R5 are independently selected from the group consisting of fluoro, chloro, bromo and iodo,
with a compound of the formula H2N-R6, optionally in the presence of a strong base, wherein R6 denotes aryl, arylalkoxy, tosyl, benzoyl, formyl, acetyl or amino; and
(b) removing R6 by hydrolysis to form a piperazine compound,
wherein the piperazine compound has formula IV,

wherein R1 denotes hydrogen atom, and R2 and R3 are as defined above.
2. The method as claimed in claim 1, wherein R6 is removed by
hydrolysis using a strong acid.
3. The method as claimed in claim 2, wherein the acid is selected from
the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid
and p-toluene sulfonic acid.
4. The method as claimed in claim 3, wherein the acid is sulfuric acid.
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5. The method as claimed in claim 4, wherein the sulfuric acid has a
concentration of about 98%.
6. The method as claimed in claim 1, wherein R2 is methyl, R3 is phenyl
and R6 is tosyl, so that the compound of formula II is a compound having
formula XII:


7. The method as claimed in claim 6, wherein R6 is removed by
hydrolysis using a strong acid.
8. The method as claimed in claim 7, wherein the acid is selected from
the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid
and p-toluene sulfonic acid.
9. The method as claimed in claim 8, wherein the acid is sulfuric acid.
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10. The method as claimed in claim 9, wherein the sulfaric acid has a concentration of about 98%.
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11. The method as claimed in claim 6, wherein (i) the piperazine compound of formula IV is reacted with 3-cyanopyridine to form 3-cyano-2-(4-methyl-2-phenyl- 1-piperazinyl) pyridine; (ii) 3-cyano-2-(4-methyl-2-phenyl-1-piperazinyl) pyridine is converted to 3-carboxy-2-(4-methyl-2-phenyl-1-piperazinyl) pyridine; and (iii) 3-carboxy-2-(4-methyl-2-phenyl-l-piperazinyl) pyridine is converted to l,2,3,4,10,14b-hexahydro-2-methylpyrazine[2,l-a]pyrido[2,3-c]benzazepine.