This application claims priority to the Indian patent application number 3767/CHE/2011 filed on Nov 03, 2011 , the contents of which are incorporated by reference in their
entirety.

FIELD OF THE INVENTION

The present invention relates to novel process for the preparation of Asenapine or its
pharmaceutically acceptable salts.

BACK GROUND OF THE INVENTION

Asenapine is having CNS-depressant, antihistamine and antiserotinin activities. It has been established that the maleate salt of Asenapine known as Org 5222 has broad spectrum, high potency serotonin, noradrenalin and dopamine antagonist. Asenapine exhibits potential antipsychotic activity and useful in the treatment of depression.

Asenapine maleate is chemically known as /ra«5'-5-Chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-lHdibenz [2, 3:6, 7] oxepino [4, 5-c] pyrrole (2Z)-2-butenedioate (1:1> and having the below structure of formula I.

US patent 4145434 first disclosed Asenapine and it's pharmaceutically acceptable salts, wherein Asenapine is prepared by reacting the compound of formula VII with methylamino-acetic acid methyl ester to get compound of formula VI, reacting the compound of formula VI with potassium tert-butoxide, followed by cyclization in acid to get compound of formula IV. Compound of formula IV is reduced in presence of magnesium in methanol and toluene to produce a mixture of a desired trans-isomer of compound of formula Ilia and an undesired cis-isomer compound of formula Hlb. The above mixture is separated by column chromatography to get desired trans-isomer of formula Ilia, compound of formula Ilia is reduced with lithium aluminum hydride to give

Asenapine free base of formula II, which is subsequently converted to maleate salt of formula I by conventional method.

The prior art process required column chromatography to separate desired trans-isomer. The column chromatography technique is not suitable in commercial scale and process involves time consuming and leads poor yield. The entire process is as shown in scheme-I.

US patent 7872147 disclosed Asenapine processes, wherein compound of formula IV is reduced in a mixture of magnesium and iodine in toluene medium to get 7:3 ratios of cis and trans-isomers of compound of formula IHb and Ilia. This mixture is subjected to ring opening reaction with base to get compounds of Villa and VIHb followed by cyclization in acid to get 2:8 ratios of cis and trans-isomers of compound of formula IHb and Ilia. This mixture is subjected to purification through column chromatography to get pure trans-isomer of formula Hla. The complete process is as shown in scheme-II.

Above mentioned prior art process involves more number of steps to prepare pure trans-isomer of formula Ilia. This process also involves column chromatography technique to get the desired quality of trans-isomer of formula Ilia. The column chromatography is difficult to handling in large scale production.

Thus there is a need for an alternate simple, less time consuming, cost effective and commercially feasible process for the preparation of Asenapine. The present invention overcomes the problems associated in prior art processes by minimizing the synthetic steps, avoiding column chromatography and it involves novel intermediates with desired isomer with improved yield and quality.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a novel process for the preparation of Asenapine maleate comprising the steps of:

a) condensing the compound of formula X with sarcosine ester to get the compound of formula XI,
b) reacting the compound of formula XI in the presence of base to get compound of formula XII,
c) cyclizing the compound of formula XII in the presence of cyclizing reagent to get compound of formula XIII,
d) reducing the nitro group of formula XIII to get the compound of formula XIV,
e) reducing the double bond of formula XIV to get the compound of formula XV,
f) ring opening of the compound of formula XV to get compound of formula XVI,
g) cyclizing of compound of formula XVI to get compound of formula XVII,
h) diazotizing of compound of formula XVII to get the compound of formula Ilia, i) reducing the compound of formula Ilia to get compound of formula II, and j) converting the compound of formula II to maleate of formula I.

Scheme-Ill

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves improved process for the preparation of Asenapine or its maleate salt. In which compound of formula X is subjected to condensation in the presence of sarcosine ester to produce the compound of formula XI, which is cyclizing in the presence of base to get the compound of formula XII and pyrrole group is subjected to cyclization in the presence of triflic acid to produce compound of formula XIII.

Reducing the nitro group in the presence of palladium carbon to get the compound of formula XIV, reducing the compound of formula XIV in the presence of magnesium and iodine to get compound of formula XV, ring opening of pyrrole group of the compound of formula XV to get trans compound of formula XVI, which is subjected to cyclization in the presence of sodium acetate to get the compound of formula XVII, diazotization of the compound XVII in the presence of sodium nitrate and cuprous chloride to get compound of formula Ilia, which is reducing in the presence of Lithium aluminum chloride and aluminum chloride to get compound of formula II. Asenapine base is converted to its maleate salt by reaction with maleic acid to get Asenapine maleate of formula I.

In one embodiment the present invention relates to an improved process for the preparation of

Asenapine maleate which comprising the steps of:

a) condensing the compound of formula X with sarcosine ester to get the compound
of formula XI,

b) reacting the compound of formula XI in the presence of a base to get compound of formula XII,

According to the present invention acid compound of formula X is converted to acid chloride by reacting with thionyl chloride in the presence of solvent, followed by reaction with sarcosine ester in the presence of a base to get amide derivative of formula XI. Compound of formula XI is cyclised in the presence of a base to get pyrrole derivative of formula XII, which is further cyclized in the presence of cylizing agent to get compound of formul XIII.

Nitro reduction of compound of formula XIII is carried out in the presence of a hydrogen and metal catalyst to get amine derivative of formula XIV. Double bond in compound of formula XIV is reduced with magnesium in presence of iodine to get the cis-trans mixture of compound of formula XV. This ratio of cis and trans in compound of formula may exist from 1.99 or 99:1. Preferably the cis and trans ratio exist in 70:30. Compound of formula XV is subjected to hydrolysis in presence of a base to get the compound of formula XVI, followed by cyclization in the presence of a buffering agent to get trans enriched compound of formula XVII. The cis and trans ratio in compound of formula XVII is around 10:90 to 30:70. Preferably the ratio of cis and trans is 20:80. Compound of formula XVII is diagtized and converted to chloro derivative using cuprous chloride to get compound of formula XVIII, followed by keto reduction in the presence of metal hydride and Lewis acid to get Asenapine free base. Asenapine free base is subsequently converted into maleate salt.

According to the present invention, solvent selected from alcohols such as methanol, keones such as acetone, esters such as ethyl acetate, ethers such tetrahydrofuron, chlorinated solvents such as dichloromethane, aprotic solvents such as dimethyl formamide, dimethylsulfoxide, acetonitrile, hydrocarbon solvents such as toluene, hexane etc.

According to the present embodiment base is selected from metal hydroxides such as sodium hydroxide, metal carbonates such as sodium carbonate, metal alkoxides such as potassium tert-butoxide, metal hydride such as sodium hydride. Cyclizing reagent is selected from polyposphoric acid or triflic acid.

Metal catalyst employed in the present embodiment such as Palladium carbon and reducing agent such as lithium aluminium hydride. The Lewis acid is employed in the present invention such as aluminium chloride.

ADVANTAGES OF THE PRESENT INVENTION

a) the present invention avoided the column chromatography purification step to get the desired quality of Asenapine, which is feasible in large scale production of Asenapine maleate,
b) the present invention produces Asenapine maleate with improved yield and quality.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXAMPLES

Example 1: Preparing the compound of formula XL

(5-Nitro-2-phenoxy-phenyl)-acetic acid of formula X (l00gm) was dissolved in dimethylformamide ( lOmL) and methylene dichloride (750mL), thionyl chloride ( 65.2 gm) was added at room temperature under nitrogen atmosphere, the reaction was maintained 1 to 2.5 hours. After completion of the reaction, methylene dichloride was concentrated the under vacuum at 30-35 °C, residue was dissolved in toluene and kept it aside under nitrogen atmosphere.
Sarcosine methyl ester hydrochloride (76.4 gm) was dissolved dimethylformamide (500mL) in another flask under nitrogen at room temperature. The solution was lowly cooled to 0-5°C; triethylamine (lllgm) was added. To this mixture the above acid chloride toluene solution was added under nitrogen at same temperature. After completion of the addition, the reaction mass temperature was raised to 20-30 °C and stirred for 2-3 hours. After completion of reaction water (500mL) was added, separated organic layer and concentrated to get residue (115gm).
Example 2: Preparing the compound of formula XII.

Potassium tert-butoxide (41.3gm) was taken in to toluene (600mL) at room temperature under nitrogen atmosphere and cooled the solution to 0-5 °C. To this solution compound of formula XI (120gm in 400mL toluene) was added under nitrogen atmosphere and the temperature was raised to 15-20°C, after completion of reaction DM water (1800mL) was added and separated the layers. The aqueous layer pH was adjusted to 6 to 6.5 with aqueous hydrochloric acid, methanol (240mL) methanol was added, stirred for one hour at room temperature and filtered the obtained solid, dried the compound in fan drier at 45-50°C till moisture content 1.0% to get title compound (60gm).

Example 3: Preparing the compound of formula XIII.

Compound of formula XII (l00gm) was added to triflic acid (200mL), raised the temperature to 105-115°C and maintained for 3-4 hours. After completion, reaction cooled to room temperature, this reaction mass was poured in to ice water (2.0 Lt) and stirred for 2 hours, filtered the obtained solid and dried at 60-65°C for 12-15 hours to get compound of formula XIII (75gm).
Example 4: Preparing the compound of formula XIV.

Compound of formula XIII (l00gm) was dissolved in methanol (2.5Lt), 10% pd/C (50% wet) was added, raised the temperature to 50°C and hydrogenation pressure (3-4 kg) was applied till the reaction completes. Catalyst was filtered concentrated methanol and n-hexane (400mL) was added to the residue, stirred for one hour at room temperature and filtered the compound dried at 45-50°C to get compound of formula XIV (75gm).

Example 5: Preparing the compound of formula XV.

Compound of formula XIV (l00gm) was dissolved in toluene (l.OLt), magnesium turnings (12.9gm) and iodine (9.1gm) were added at room temperature, the temperature was slowly raised to 60-70°C, followed by methanol and maintained the stirring for 2hrs. Magnesium turnings in seven intervals (2.59g X 5) were added at 60-70°C to complete the reaction. The mixture was diluted with DM water (500mL), pH of the solution was adjusted to 7.0-8.0 with aqueous hydrochloric acid and filtered the solids through celite bed, separated the toluene layer and concentrated to get crude compound of formula XV (65gm).

Example 6: Preparing the compound of formula XVI.

Compound of formula XV (lOOgm), ethanol (1.5 Lt) and potassium hydroxide (340gm) were taken in flask at room temperature, raised the reaction mass to 100-105°C and maintained for 3-5 hours. After completion, cooled the reaction mass to 20-30°C and DM water (500mL), toluene (500mL) were added, separated the layers. Aqueous layer pH was adjusted to 1-2 with aqueous hydrochloric acid, toluene was added and separated the layers, concentrated ethanol/water mixture to get wet solid of compound of formula XVI (240gm).

Example 7: Preparing the compound of formula XVII.

Compound of formula XVI (2.0gm), toluene (15mL) and sodium acetate (l.Ogm) were taken at room temperature, raised the temperature to 100-110°C and maintained for 2-3 hours. After completion, reaction mass was cooled to room temperature and filtered the solids through hyflow bed, concentrated toluene layer under reduced pressure to get solid material (0.5gm).

Example 8: Preparing the compound of formula Ilia.

Compound of formula XVII (1.0 gm), concentrated hydrochloride (5mL) were taken in a flask and cooled the mass to 0-5 °C. To this sodium nitrate solution was added (0.271 gm dissolved in 5mL DM water), stirred the reaction mass for 10-15 minutes (diazonium salt solution). Cuprous chloride (1.41gm) and con.hydrochloride (5mL) were taken in another flask at 0-5 °C; the above diazonium salt solution was added at same temperature and maintained for 30 minutes. Slowly raised the temperature to 50°C, maintained for one hour, after completion, reaction mass cooled to room temperature and filtered the obtained solid (0.5gm).

Example 9: Preparing the compound of formula II.

Aluminiumchloride (0.080gm) was added to tetrahydrofuron (5mL) at room temperature and slowly cooled the reaction mass to 0-5°C under nitrogen atmosphere and stirred to get clear solution. Lithiumaluminium hydride solution (10% solution 1.6mL) was slowly added at same temperature under nitrogen atmosphere and stirred the mixture for 15-25 minutes at same temperature. To this mixture compound of formula Ilia (0.5gm in 5mL THF) was slowly added maintained stirring for one hour. After completion the reaction, saturated sodium sulphate solution (lOmL) was slowly added and reaction mixture was extracted with ethyl acetate, separated the organic layer and distilled under vacuum completely to get Asenapine free base (0.4gm).

Example 10: preparing the Asenapine maleate of formula I.

The compound of formula II (0.4 gm) was dissolved in ethanol (30mL), treated with charcoal and the solution was heated to 60-65°C. Maleic acid solution (5gm dissolved in 50mL ethanol) was added at same temperature and maintained for 30-40 minutes. The reaction mass temperature was cooled to 23-30°C to get slurry and further cooled to -5 to -10°C, maintained stirring for 2-3 hours. The obtained solid was filtered, washed with chilled ethanol and dried the product under reduced pressure at 40-45°C to get Asenapine maleate of formula I (0.2g).

We claim:

1. An improved process for the preparation of compound of formula Ilia, which comprising of:

2. The process according to claim 1, wherein base is selected from metal hydroxides such as sodium hydroxide, metal carbonates such as sodium carbonate, metal alkoxides such as potassium tert-butoxide, metal hydride such as sodium hydride.

3. The process according to claim 1, wherein cyclizing reagent is selected from polyposphoric acid or triflic acid.

4. The process according to claim 1, wherein the reducing reagent in step (d) is carried by palladium carbon and hydrogen.

5. The process according to claim 1, wherein the reducing reagent in step (e) is reducing agent magnesium and iodine.

6. The process according to claim 1, wherein the diazotization reagent in step (h) is sodium nitrate and cuprous chloride.

7. The process according to claim 1, wherein the reducing reagent in step (i) is metal hydride and Lewis acid.

8. The process according to claim 8, wherein the metal hydride such as sodium hydride.

9. The process according to claim 8, wherein the Lewis acid such as aluminium chloride.