FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A Novel process for Miratazapine Intermediate."
2. APPLICANT (S)
(a) NAME: Genesen Labs Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Genesen Labs Ltd,
R-75, TTC Industrial estate,
Thane -Belapur Road
Navi Mumbai. -400701.Maharastra (India).
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.
1

A Novel process for Miratazapine Intermediate.
Field of Invention:
This Novel method of synthesis for Miratazapine intermediate, an antidepressant drug. It also concern to novel intermediate with a heavy cost reduction process without using hazardous raw materials .This is also intend to the Industrially applicability with a non polluted waste.
Background of Invention:
Miratazapine, a well known Antidepressant drug suitable for oral administration. Miratazapine, belongs from piperazinozapine group of compound, it has a tetracyclic chemical structure unrelated to the other class of antidepressant drug such as Selective Serotonin reuptake inhibitors (SSRIs).

wflg
Miratazapine having a fallowing structure:
2.

1 methyl 3 phenyl piperazine is a key starting material or intermediate in Miratazapine which is disclose in a Roderick W.R. et all Journal of medicinal chemistry 9, 1966,181-185. This publication reported a synthesis of 1 methyl 3 phenyl piprazine with a very low yield 9-30 % with a expensive raw materials.

C6H5 CH—C—OC2H5
Br O
(Ethyl a-bromophenylacetate)

H2N NH2
(Ethylenediamine)

Na/EtOH

H
.C6H5
H
(2-oxo-3-phenylpiperzine)

L1AIH4



C6H5
CSH5
N
I CH3
(l-methyl-3-phenylpiperazine)

CH3I/TEA/Acetone

(2-phenylpiperazine)

In this above publication mentioned scheme a yield is very low due to not occurring a selective methylation at 1 position . A mixture of products like 1-methyl 2 phenyl piperzine and 1,4 dimethyl 2 phenyl piprazine along with 1 methyl 3 phenyl piprazine so there is a need of extended purification.
U.S. Pat. No. 6,495,685 has described the preparation of l-Methyl-3-phenylpiperazine by reacting N-(2-chloroethyl)-N-methyl-.beta.- -chloro-.beta.-phenylethylamine (the dichloride) of Formula (A) with ammonia.

3

CI
H3C N CI
<
C6H5
This dichloride of Formula (A) has been prepared by chlorination of the corresponding diol, N-(2-hydroxyethyl)-N-methyl-.beta.-hydroxy-.beta.- -phenylethylamine of Formula (B).
In U.S. Pat. No. 6,495,685, this diol has been obtained by reacting styrene oxide with N-methylethanolamine. However, the described preparation of diol results in the formation of substantial amount of isomeric compound of Formula (B) due to non-selectivity in this reaction.

H3C N

<
C«H5

The presence of isomeric diol of Formula (B) results in the formation of corresponding 1-methyl-2-phenylpiperazine isomer which contaminates the product and results in lower productivity.
In the U.S. Pat. No. 6,339,156 the same dichloride of Formula (A) has been treated with p-toluenesulfonamide to obtain tosyl piperazine which is hydrolyzed to produce l-Methyl-3-phenylpiperazine. However, preparation of dichloride and its isomeric purity has not been discussed in this US Patent.
In US Pub appl. No. 2004/0242879 Al disclose a method of preparation of 1 methyl 3 Phenyl piperazine by mehtylation of 4 Benzyl 2 oxo 3 phenyl piprazine and finally deprotection of benzyl group gives a title compound . As concerning this patent the use of expensive raw materials like LiAlH4 and CH3I, as well as hazardous , explosive raw material like NaH is used in this preparation . The major disadvantage of this process is that, Hydrogenation for deprotection of benzyl group, as concerning a industrial process hydrogenation is a very difficult and risky due to maximum chances of explosion .
4

In WIPO Patent no.WO02/ 090339 reported a preparation of 1 methyl 3 Phenyl piperazine a key intermediate of Miratazapine , by catalytic reduction of 1 Benzyl 4 methyl 2 phenyl piprazine but it is highly expensive and risky due to expensive raw materials and hydrogenation.
In US pat. No. 6852855 disclose a process for preparation of 1 methyl 3 phenyl piperazine , in which dichloro compound (B- chloro -N- methyl -N- chloro ethyl phenalamine) treated with PTSA (Para-toluene sulphonamide) in presence of sodium hydride at temp 70-80 DC for over night to get a tosyl piperazine and finally reflux at 120 °C with cone, sulphuric acid to get a title compound. According to above process time parameter and explosive material like sodium hydride is used and also major disadvantage is that, the quantity of Sulphuric acid used for getting title compound is very high (Tosyl piperazine: Sulphuric acid 1:5%) so after completion of reaction there is a major disposal problem for Industrial scale.
In view of prior arts describe above it has been seen that , it desirable to have a method for preparation of 1 methyl 3 phenyl piprazine having a less steps, high yield and non explosive raw materials as well as well efficient and variable to industrial scale.
Object of Invention:
The main object of present invention is that to have a efficient and cost effective novel process for preparation of 1 methyl 3 phenyl piperazine which is a key intermediate for antidepressant drug Miratazapine.
Another object of present invention is that, a novel process which is applicable to large (industries) scale with non explosive and non expensive raw materials.
Another object of present invention is that, to avoid lengthy steps and Environment friendly process (without disposal problem).

5
Statement of Invention:
This novel process mainly concern with the efficient and industrially applicable process as well as an environment friendly (without disposal problems) non explosive, non expensive and non hazardous materials used.
Summary of Invention:
It has been seen that, from long back it needs to a easy and cost effective, improve and industrially applicable(without disposal problems) process for preparation of 1 methyl 3 phenyl piprazine a key intermediate in antidepressant drug , Miratazapine.
According to present invention, which provides an efficient process for preparation of 1 methyl 3 phenyl piperazine comprises:
1) Mixing of 1 mole of Benzaldehyde with a 1.2 mole of Chloroehtalamine in step -I at reflux temp for 24 hrs to get an intermediate (I) by using conventional separating method.
2) In step -II an intermediate -I recovered from step -I, with a 1 -Chloro N- methyl methylamine at a reflux temp in ethylene dichloride as a reaction medium for 5-8 hrs for complete conversion of starting material.
3) Extract the whole reaction mass at pH 7-11 by ethyl acetate and evaporate under vacuum to get a title compound.
Alternate method:
1) Mixing of 1 mole of Benzaldehyde with a 1.2 mole of N-methylethane-1,2 diamine in step -I at reflux temp for 24 Hrs to get an intermediate (la) by using conventional separating method.

6

2) In step -II an intermediate -I recovered from step -I, with a dibromo methane at a reflux temp in ethylene dichloride as a reaction medium for 5-8 hrs for complete conversion of starting material.
3) Extract the whole reaction mass at pH 7-11 by ethyl acetate and evaporate under vacuum to get a title compound.
In the developed process the retained 1 methyl 3 phenyl piperazine is derived sans impurities. Besides, as stated earlier this 1 methyl 3 phenyl piprazine is highly imperative for preparation of the antidepressant drug , which known as Miratazapine. In the obtained process 1 methyl 3 phenyl piprazine is in high yield and free from impurities.
Details description of invention:
The present invention provides a novel process for preparation of piperazine ring derivatives specifically, 1 methyl 3 phenyl piperazine (Formula -I) which is a key intermediate for anti depressant drug Miratazapine , which has been disclosed in US patent No 4062848 Vander burg et all. The present invention comprises a compound formula (II)
Formula (II) Where as;
P is oxygen or sulphur .
R is hydrogen or alkyl.

7
Reacting with compound formula (Ilia) or (III b)
^^/ Y OR ^^ ^N
I
Formula (Ilia) R1R1
Formula (Illb)
Where as in (Ilia):
X is a selected from a group of Chloro, bromo, fluro , iodo , acyl or acetoxy.
Y is a group from amine , imine or imide.
Rl = R2 is a hydrogen or alkyl.
Where as in (Illb);
Y is same as defined above.
Rl = R2 same as defined above.
From theses compounds of formula (Ilia) and (Illb) further comprises a compound formula (IVa) and (IVb) respectively from compound (Ilia) and compound (Illb).

8


-R2
and

^^

N'
N-I R1R1R3R3

Formula (IVa)

Formula (IVb)

Where as;
X is same as defined above.
R1=R2=R3 is same as defined above.
Finally a compound of formula (IVa) and compound formula (IVb) with a compound of formula (Va) and (Vb) respectively .

X'

/

R2

Formula (Va)

and

X X
Formula (Vb)

Where as in formula (Va);
X is same as defined above.
Rl= R2 is same as defined above.
Where as in formula (Vb)

.3

X is same as defined above.
Gives a title compound of formula (I)

Where as;
Rl = R2 is same as defined above.
In preferred embodiment present invention relates to the process for preparation of compound formula (I).

I
CH? Formula (I)
The above embodiment well elaborates by providing examples with scheme.

10

Scheme -I
Step -I

benzaldehyde

CI
NH2 2-chloroethanamine

N-^CI

2-chloro-A/-[(1£)-phenylmethylene]ethanamine

Step -II


^^

XH,
CI
1-chloro-A/-methylmethanamine

<^^

1-methyl-3-phenylpiperazine
Example -1
Step-1
a) Charge a 106.12 gm (1 mole) of Benzaldehyde in 100 ml toluene in 500 ml round bottom flask with well fitted dean-stark apparatus and add 95.42 gm (1.2 mole) 2 chloro ethalamine slowly.
b) Heat the reaction mass up to reflux for 24 hrs and collect a equivalent amount of water after completion of reaction ,check the complete conversion of raw material by TLC.
completion of reaction ,check the complete conversion of raw material by TLC.

11

c) After completion of reaction extract the whole residue by 300 ml Ehtylene dichloride and wash this organic layer by 5 % NaHC03.
d) Finally dry this organic layer over sodium sulphate and distilled out by conventional method of distillation to get a oily residue of l-chloro-Af-[(lE)-phenylmethylene]methanamine for further stage .
Yield - 75- 85 %.
Step -II
a) Take a 167.23 gm l-chloro-iV-[(l£)-phenylmethylene]methanamine received from previous stage in 500 ml round bottom flask fitted with water condenser add 94.93 gm 1-Chloro-N-methylmethanamine with 300 gm ethylene dichloride to above.
b) Stirr the reaction mass for 10 minutes to get a homogeneous mixture.

c) Add 9.25 gm(0.25 mole) Sodium boro- hydride slowely for initiation of reaction strong exotherm will observe.
d) Heat the whole content slowly up to reflux for 5-8 hrs, check the completion of reaction by TLC.
e) After completion of reaction cool the reaction mass up to room temp and evaporate ethylene dichloride under vacuum.
f) Add 200 ml water slowly by avoiding exotherm and make a pH of reaction mass in between 7 toll.

12
g) Extract with 200 ml ethyl acetate, dry over the sodium sulphate and evaporate under vacuum to get a title compound.
Yield = 75-80 %.
Scheme -II
Step -I


N—CH3
,CHO
benzaldehyde

+ H2NV
/V-methylethane-1,2-diamine

/V-methyl-M-IO £)-phenylmethylene]ethane-1,2-diamine
Step -II


N CH,
+ Br Br
dibromomethane

H
I CH3

r^

/V-methyl-A/'-[(1 £)-phenylmethylene]ethane-1,2-diamine

1-methyl-3-phenylpiperazine

Example-2
Step-1
a) Charge a 106.12 gm (1 mole) of Benzaldehyde in 100 ml toluene in 500 ml round bottom flask with well fitted dean-stark apparatus and add 88.94 gm (1.2 mole) N methyl ethane -1,2 -diamine slowly.
13
b) Heat the reaction mass gently up to reflux for 24 hrs and collect equivalent amount of water after completion of reaction ,check the complete conversion of raw material by TLC.
c) After completion of reaction extract the whole residue by 300 ml Ehtylene dichloride and wash this organic layer by 5 % NaHC03.
d) Finally dry this organic layer over sodium sulphate and distilled out by conventional method of distillation to get a oily residue of JV-methyl-A/'-[(lE)-phenylmethylene]ethane-l,2-diamine for further stage without extended purification.
Yield = 75- 85 %.
Step -II
a) Take a 162.23 gm ]V-methyl-JV'-[(l£)-phenylmethylene] ethane-1,2-diamine received from previous stage in 1000 ml round bottom flask fitted with water condenser add 225.43 gm ethylene dibromide with 200 gm ethylene dichloride to above.
b) Stir the reaction mass for 10 minutes to get a homogeneous mixture.

c) Add 9.25 gm(0.25 mole) Sodium boro- hydride slowely for initiation of reaction strong exotherm will observe.
d) Heat the whole content slowly up to reflux for 5-8 hrs, check the completion of reaction by TLC.
e) After completion of reaction cool the reaction mass up to room temp and evaporate ethylene
dichloride under vacuum

14
f) Add 200 ml water slowly to avoid exotherm and make a pH of reaction mass in between 7 to 11 .
g) Extract with 200 ml ethyl acetate, dry over the sodium sulphate and evaporate under vacuum to get a title compound.
Yield = 75-80 %.

15
Claims:
1) The method for preparing compound formula (Ila and II b)


N—R4
^^

Formula (Ila)

Formula (lib)

Where as,
R = R3 represent a Hydrogen, methyl ethyl, propyl.
X = represent selectively halide group or alkoxy group Chloro , fluro, bromo, lodo, acetoxy or acyl.
R4 = represent alkyl.
Where as,
R = represent a Hydrogen or alkyl.
Comprising a step of reacting compound formula


16

With a compound of formula or its salt.
OR A^ /\ ^R4
'NT I R
Where as,
X = represent selectively halide group or alkoxy group ; Chloro , fluro, bromo, lodo, acetoxy or acyl.
A = represent amino , imine , amide.
2) The method of claim 1 wherein,
R is hydrogen.
X is Chlorine or bromine. R3 is Hydrogen. R4 is methyl. A is amine.
3) The method in claim 1 reacction performed in methylene dichloride, ethylene dichloride, diethyl ether, toluene acetonitrile, methanol ,tetrahydrofuran .
4) The claimed in claim 3 reaction performed in Ethylene dichloride and Toulene at temp of Reflux.

17
5) The method in claim 1 , furthermore comprising a step of condensation of compound formula
(Ila) and (lib) with compound formula (Ilia) and (Illb) respectively.

and x X
Formula (Ilia)
Formula (Illb)

Where as,
R= represent hydrogen or alkyl.
R4 - represent alkyl.
X = represent chloro, fluro, bromo, iodo , acetoxy, acyl.
6) The method of claim 5 wherein,
R is a Hydrogen
R4 is Mehtyl.
X is Chlorine or Bromine.

18
7) A novel and cost effective process for Miratazapine intermediate as substantially describe herein with reference to forgoing example 1 and 2.

19

Abstract:
The present invention mainly describes a novel process with novel intermediate, industrially applicable without hazardous raw materials. The compound formula (I):

I CH3
Which is mainly used in antidepressant drug, Miratazapine disclosed.

20