FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10,and Rule 13]
Title
IMPROVED PROCESS FOR THE PREPARATION OF DIBENZOXEPINO DERIVATIVE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality : Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the invention:

IMPROVED PROCESS FOR THE PREPARATION OF DIBENZOXEPINO DERIVATIVE
FIELD OF THE INVENTION:
The present invention relates to an improved enantioselective process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole-1 one with an improved yield and quality. Trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole-l-one is useful intermediate for the preparation of Asenapine and pharmaceuticals acceptable salt.
BACKGROUND OF THE INVENTION:
Asenapine is an atypical antipsychotic. Asenapine is a new 5-HT2A- and D2-receptor antagonist that is being developed by Organon International for the treatment of schizophrenia and acute mania associated with bipolar disorder. Preliminary data indicate that it has minimal anticholinergic and cardiovascular side effects, and minimal weight gain.
Asenapine having compound of formula (I) was first disclosed in US Pat. No. 4,145,434.

A general methodology for the preparation of Asenapine and its intermediates was described in US Pat. No. 4,145,434, and synthetic method for the preparation of Asenapine and radiolabeled derivatives was also described in Journal of Labelled Compounds and Radio pharmaceuticals, (1994), vol.XXXIV, No.9,845-869 produce Asenapine.
US Pat. No. 4,145,434 discloses general methodology for the preparation of Asenapine by condensation of formula (II) 2-(4-chlorophenyl)acetyl chloride with N-methyl glycin ester

(III) in presence of triethyl amine and N,N-dimethyl formamide to yield compound of formula (IV) ethyI[{[2-(4-chlorophenoxy)phenyl]acetyl}methylamino]acetate, followed by cyclization in presence of potassium tert butoxide in toluene as solvent to produce compound of formula (V) [3-[2-(4-chlorophenoxy)phenyl]-l-methyl-pyrrolidine -2,4-dione] and further cyclization using polyphosphoric acid to yield compound formula (VI) [11-chloro-2,3-dihydro-2methyl-lH-dibenzo[2,3:6,7]oxepino [4,5-c]pyrrol-l-one], followed by selective reduction in presence of magnesium and methanol to yield compound formula (VII) [trans-5-chloro-2,3,3a,2 1b-tetrahydro-2-methyl 1 H-dibenzo [2,3:6,7]oxepino[4,5-c] pyrrol-lone] (10% from formula VI), which is further reduced by LiAlH4 or diborane followed by separation of cis & trans isomer by Si02 column chromatography to yield compound of formula (I) [trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7] oxepino [4,5-c]pyrrole maleate] having melting point of 141°C, as shown in Scheme-1.
Scheme-1

(a) halogenation using SOCl2 (b) condensation in triethylamine & N,N-dimethyl formamide (c) cyclization in presence of toluene and potassium tert-butoxide at 0°C. for 16 hrs. (d) cyclization in presence of poly phosphoric acid at 125°C. for 4 hrs (e) selective reduction in presence of magnesium and methanol (f) reduction in presence of LiAlH4 or diborane.
US Pat No. 4,145,434 and Journal of Labelled Compounds and Radio pharmaceuticals, (1994), vol.XXXIV, No.9,845-869 disclose general methodology for reduction of double bond of pyrazole ring by treatment with excess mole of magnesium in methanol to produce a

mixture of a desired trans-isomer and an unwanted cis-isomer in a 1:8 ratio, which is further separated by column chromatography.
An alternative route of making trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-(IH)-dibenzo [2,3:6,7]oxepino[4,5-c] pyrrol-1-one (VII) is disclosed in example-8 of PCT Pub. No. 2006106136 in which mixture of cis & trans-5-chloro2,3,3a,12b-tetrahydro-2-methyl-lH-dibenzo [2,3:6,7] oxepino [4,5-c] pyrrol-1-one is treated in metalalcoholic solution with strong alkaline base to open the ring and subsequently trans isomer is isolated and cyclized to give tran-5-chloro-2,3,3a,12b-tetrahydro-2-methyllH-dibenzo[2,3:6,7]oxepino[4,5-c] pyrrol-1-one (VII) as shown in Scheme-2.
Scheme-2

According to PCT Pub. No. 2006106136, an unfavorable product ratio can be improved by subsequent partial isomerization of unwanted cis-isomer in to the trans-isomer by 1,5-diazabicyclo[4.3.0]non-5-in (DBN), which is further subjected to column chromatography over silica gel to separate the isomers. The said process requires repetition of separatation and recrystallization to produce trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyllH-dibenzo [2,3:6,7] oxepino[4,5-c]pyrrol-l-one (VII) in overall yield of 35-39% starting from the 11-chloro-2,3-dihydro-2methyl-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one(VI).

Tetrahedron letters, 44 (2003); page292S-2926 discloses the reduction of Formula-A in metallic magnesium and methanol at 60°C temperature, which results in erythro and threo product in proportion of (85:15) with yield of about 40%.

In Advanced organic chemistry, Jerry March, Fourth edition; page586 discloses a racemization process where an optically active compound, in which the chirality is due to an asymmetric carbon a to a carbonyl group, is treated with acid or base. If there is another asymmetric centre in the molecule, the less stable epimer can be converted to the more stable one in this manner, and this is often done. For the acid catalyzed process, exchange or equilibration is accomplished only if the carbonyl compound is completely converted to the enol and than back.

As per the process disclosed in the US Pat. No. 4,145,434, reflux temperature is required for activation of excess amount of magnesium metal. It has been observed that below reflux temperature, hydrogen gas evolution takes place and thereby double bond reduction does not occur. It means for activation of excess amount of magnesium metal, reflux temperature is required. It has been observed that at reflux temperature activation of magnesium metal is enormous and uncontrolled and amount of hydrogen gas evolved is very high, which makes it difficult to control during scale-up because of excess amount of magnesium. At reflux temperature higher amount of unknown impurity formation was observed and also conversion of trans to cis-isomer takes place.

As per the process disclose in the US Pat. No. 4,145,434 the use of the magnesium metal in 35-45 moles during reduction of double bond in ring pH of the reaction mass shifted toward basic side (about 8-11) which result in formation of more undesired cis isomer as well as few unknown process impurities.
The critical factor in this reaction is ratio of trans and cis isomer of 5-chloro2,3,3a,12b-tetrahydro-2-methyllH-dibenzo[2,3:6,7]oxepino[4,5-c] pyrrol-1-one (VII) which depends on different experimental condition. Inventors of present invention have surprisingly discovered experimental condition by using the optimum quantity of magnesium metal, temperature of the reaction, pH of the reaction mass during reaction and use acid catalyst such as acetic acid or formic acid helps to carry out the reaction at lower temperature, due to this thermal degradation, desire trans isomer does not takes place and thus more amount of trans isomer formation takes place as compared to prior art process, which renders the process of present invention cost effective and commercially viable for the preparation of Asenapine of formula CD-SUMMARY OF THE INVENTION:

comprises, the selective reduction of compound of formula (VI)
In one aspect of invention, the specification discloses an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyllH-dibenzo[2,3:6,7] oxepino [4,5-c] pyrrol-1-one of formula (VII)



(b) converting the compound obtained in step (a) into Asenapine of formula (I) and pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION:
The terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
As used herein, the "selective reduction" means reduction of double bond in a ring compound of formula (VI) in to trans-isomeric form of formula (VII).

As used herein, the term "isolating" means filtration, distillation, cooling, stripping, vacuum drying, crystallization of compound and recovery and the like.
The inventors of this invention have surprisingly found that evolution of gas occurs in a control way using activation of magnesium metal at 0° to 25°C.with catalytic amount of acetic acid, which results in formation of less impurities, faster reaction takes place at low temperature and trans isomer remain stable.
It has been also observed that use of 4 moles of acetic acid makes the pH of the reaction in acidic side (4 to 6) and therefore the impurity formation was observed very less. It has also been observed that if more quantity of acetic acid is used, the magnesium reacts with the acetic acid and the reaction mass becomes very thick mass which hinders the reaction.
The intermediates compound of formula (VI) is commercially available or it can be prepared by method known in prior art. The preparation of compound of formula (VI) is given in US Pat. No. 4,145,434.
The process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyI-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole-l-one and it's conversion to Asenapine is depicted in reaction Scheme-3 as below.
Scheme-3:

The selective reduction of compound of formula (VI) includes less than or equal to 12 mole of magnesium metal with acetic acid with acetic acid in an inert solvent at a temperature ranging from 0° to 25°C.

The present invention further provides process for the preparation of Asenapine of formula (I) comprising ; (a) selective reducing the compound of formula (VI) in presence of less than or equal to 12 mole of magnesium metal with acid catalyst in an inert solvent at temperature ranging from 0° to 25°C. to give compound formula (VII), (b) converting the compound obtained in step (a) in to Asenapine or pharmaceutically acceptable salt thereof.
The reaction can be carried out preferably ranging from one to five hours.
It has been also observed that use of acid catalyst makes the pH of the reaction in acidic side (4 to 6) and therefore the impurity formation was observed very less. The acid catalyst from the groups includes Acetic acid or Formic acid and. preferably acetic acid.
The acid catalyst used in the method of the invention is preferably 1 to 4 moles.
The selective reduction reaction can be carried by use of magnesium metal, acid catalyst at controlled pH of reaction mixture and at a controlled temperature.
The solvent used can be organic solvent. The solvent selected from the group includes dimethoxyethane, 1,3-dioxalane, ethylacetate, acetonitrile, dimethylformamide; diemthylacetamide; dimethylsulfoxide; dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, etc. ,. halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethylene etc. , ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone, etc. , ethers such isopropyl ether, methyl tertiary butyl ether, diethyl ether or petroleum ether, or carboxylates such ethyl acetate, C1-C4 alcohol such as Methanol, Ethanol, isopropyl alcohol, and the like or a mixtures thereof. Preferably methanol.
Magnesium metal can be used in different particle and mode of addition in reaction mass. Addition of magnesium metal may be in a lot or in lot wise.

The isolation of trans isomer from mixture of cis & trans-isomer is carried out by solvent crystallization or by column chromatography method.
The inventors of this invention have surprisingly found that after reduction of formula (VI), ratio of trans and cis isomer is 1:3 and after isomerization treatment with 1,5-diazabicyclo[4.3.0]non-5-in (DBN)3 the ratio of trans and cis isomer is 1:1.
In another aspect, conversion of formula (VII) in to compound of formula (I) includes solvents like diethyl ether and diisopropylether, which results in the formation of less than 1.5 % cis-isomer as compared to 20 to 30% as per US Pat. No. 4,145,434
Optionally, the obtained trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7] oxepino[4,5-c]pyrrole of formula (I) may be recovered by conventional means known in the art such as extraction, evaporation, filtering or distillations.
The completeness of reaction can be checked by using any known analytical method i.e. TLC or PLC.
The maleate salt of the Asenapine (I) can be obtained in general by mixing Asenapine and maleic acid in a suitable solvent, as per the processes known in art, to produce the Asenapine maleate.
The invention will now be described in connection with certain preferred embodiments in the following examples. The invention may not be so construed so as to limit it only to these particular embodiments. Thus, the following examples, which include preferred aspects, will only serve to illustrate the practice of this invention.
Example-l
Preparation of trans-5-chloro-2-metbyl-2,3,3a,12b-tetrahydro-lH-dibenzo [2,3:6,7]
oxepino[4,5-c]pyrrole-l-one (VII).

10.0 gm (0.0336 moles) of ll-chloro-2,3-dihydro-2methyl-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one (VI) was added to 500.0 ml of methanol at room temperature. The mixture was stirred at room temperature for 5 minutes and then 8.0 gm (0.133 moles) of acetic acid was added thereto. The mixture was cool to 20°-25°C. and add Magnesium 8.1 gm (0.333 moles) in four lots in 2 hours. Stir for 2 hours at 20°-25°C. till reaction completed. The methanol was completely distilled off from resulting mass under vacuum below 350C. (crude material weight was 11.0 gm having 25-30 % trans-isomer). The separate trans isomer by column chromatography in ethyl acetate and n- hexane to afford trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo [2,3:6,7] oxepino[4,5-c]pyrrole-l-one (VII) ( Yield: 2.8 gm) and purity > 98%. (% of trans : cis is 25% : 75%)
Example-2
Preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo [2,3:6,7]
oxepino[4,5-c] pyrrole (I).
1.0 gm (0.2635 moles) of lithium aluminum hydride was added to 150.0 ml. of diisoporpyl
ether at room temperature. The mixture was cooled to 0 to 5°C. and added 1.0 gm (0.00334
moles) of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-
c]pyrroIe-l-one (VII). 50.0 ml of diethyl ether was Added in 30 mint, at 0 to 5°C. in
reaction mass. The mixture was stirred at 0° to 5°C. for 1 hour and then 5.0 ml of water was
added thereto. Stir for 20 minutes at 0° to 5°C. The solvent was distilled off from resulting
mass under vacuum below 35°C.( crude material weight was 0.9 gm, having 50-60 % Trans-
isomer). The separated Trans isomer by column chromatography in ethyl acetate and n-
hexane afford trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (I) ( Yield: 0.4 gm). (% of trans : cis is 85% : 15%)
Example-3
Preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrabydro-lH-dibenzo [2,3:6,7]
oxepino[4,5-c]pyrrole maleate (Asenapine maleate).

0.4 gm (0.0014 moles) of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (I) was added in 2.0 ml of ethanol and stirred at 25-35°C. for 10 minutes, followed by addition of 0.18 gm (0.0016 moles) of maleic acid at 25°-35°C. The mixture was stirred at 25°-35°C. for 15 minutes. Distilled out solvent under the vacuum below 35°C. The resulting residue was mixed with 4.0 ml. of ethyl acetate and 8.0 ml. of diisopropyl ether within 20 min and stirred for 1.0 hours at 25°-35°C.. Solid was filtered with suction, washed bed with mixture of chilled ethyl acetate and diisopropyl ether (1:2) dried the material at 25°-35°C. to get Asenapine maleate (weight 0.3 gm) HPLC purity : 89.53 %. Further it was recrystallized from Ethyl acetate /n-hexane to obtain highly pure Asenapine maleate (weight 0.15 gm). (% of trans : cis is 99% : 0.8%)
Example-4
Isomerization of cis-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]
oxepino[4,5-c] pyrrole-1-one (Vll-cis )
120.0 gm (0.4 moles) of cis-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-l-one (Vll-cis) was added to 4800.0 ml of toluene at room temperature. Added 19.8 gm (0.1601 mole) of l,5-diazabicyclo[4.3.0]non-5-in (DBN) in reaction mass at 25°-35°C. The mixture was stirred at 25° to 35°C. for 2 hour. Cool the reaction 0° to 5°C. Stir for 20 minutes at 0° to 5°C.. Added 2400.0 ml water in reaction mass at 0° to 5°C..Adjust pH 4 using acetic acid at 0° to 5°C Stir the reaction mass for 20 min. separate out the organic layer organic layer wash with water thrice The solvent was distilled off from resulting mass under vacuum below 35°C.( crude material weight was 120 gm, having 25-35 % trans-isomer). The separated trans isomer by column chromatography in ethyl acetate and n- hexane afford trans-5-chIoro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (I) ( Yield: 28 gm). (% of trans : cis is 40% : 20%)

We claims:

comprises: the selective reduction of compound of formula (VI)

1. A process for the preparation of a compound of formula (VII):
with magnesium metal in the presence of acid catalyst in inert solvent.
2. A process for the preparation of Asenapine of formula (I) and its pharmaceutical acceptable salt thereof:

comprises the steps of:
(a) Selective reduction of of trans-5-Chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole-l-one of formula (VI) with magnesium metal in the presence of acid catalyst in inert solvent to give compound of formula (VII),


(b) converting the compound obtained in step (a) into Asenapine of formula (I) and pharmaceutically acceptable salt thereof.
3. The process according to claim 1 or 2, wherein the solvent used in reduction is selected from the group comprising of dimethoxyethane, 1,3-dioxalane, ethylacetate, acetonitrile,; dimethylformamide; diemthylacetamide; dimethylsulfoxide; dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, etc. , halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethylene etc. ,ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone, etc. , ethers such isopropyl ether, methyl tertiary butyl ether, diethyl ether or petroleum ether, or carboxylates such ethyl acetate, C1-C4 alcohol such as Methanol, Ethanol, isopropyl alcohol,or a mixtures thereof.
4. The process according to claim 1 or 2, wherein the acid catalyst is acetic acid or formic acid.