WO2013035109A1 - Improved process for the preparation of asenapine maleate - Google Patents

Improved process for the preparation of asenapine maleate Download PDF

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Publication number
WO2013035109A1
WO2013035109A1 PCT/IN2012/000591 IN2012000591W WO2013035109A1 WO 2013035109 A1 WO2013035109 A1 WO 2013035109A1 IN 2012000591 W IN2012000591 W IN 2012000591W WO 2013035109 A1 WO2013035109 A1 WO 2013035109A1
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formula
compound
isomer
acid
trans
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PCT/IN2012/000591
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French (fr)
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Shankar Rama
Jitendra Sharma
Virupakshachar Mouneshwarachar AGADI
Surya Nageswara Rao ACHANTA
Venkata Naga Vikas Chandra Dev RAVI
Venkanna DACHEPALLY
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Mylan Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to an improved process for the preparation of Asenapine maleate with an improved yield and purity without using column chromatography.
  • 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 frans-5-Chloro-2-methyl-2, 3, 3a, 12b- tetrahydrp- I Hdibenz [2, 3:6, 7] oxepino [4, 5-c] pyrrole (2Z)-2-butenedioate (1: 1J and having the below structure of formula I.
  • US patent 7872147 disclosed Asenapine process, wherein compound of formula IV is reduced in a mixture of magnesium and iodine toluene medium to get 7:3 ratios of cis and trans-isomers of compound of formula lllb and Ilia. This mixture is subjected to ring opening reaction with base to get compounds of Villa and Vlllb followed by cyclization in acid to get 2:8 ratios of cis and trans- isomers of compound of formula lllb and Ilia. This mixture is subjected to purification through column chromatography to get pure trans-isomer of formula Ilia. The complete process is shown in scheme-ll.
  • the present invention overcomes the problems associated in prior art processes by minimizing the synthetic steps, avoiding column chromatography and it involves simple purification method to get the desired isomer with improved yield and quality.
  • One aspect of the present invention is to provide an improved process for the preparation of Asenapine maleate comprising the steps of:
  • Another aspect of the present invention is to provide Asenapine maleate having the particle size of d 90 less than 100 microns, dw less than 50 microns and d 10 less than 15 microns.
  • the present invention involves improved process for the preparation of Asenapine maleate, in which compound of formula V is subjected to cyclization in the presence of an strong acid to produce the compound of formula IV, reducing the compound of formula IV to get the cis, trans mixture of formula III, separating the trans-isomer of formula Ilia from the mixture and subjecting to reduction reaction, followed by salt formation with hydrobromic acid to get Asenapine hydrobromide of formula lla. Reacting Asenapine hydrobromide of formula Ha with maleic acid to get Asenapine maleate with improved yield and quality.
  • 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2, 4-dione of formula V is added to strong acid and the resulting mixture heated to 100 to 130°C, preferably to 110- 115°C and maintained for 3-6 hrs at same temperature.
  • the strong acid used in the cyclization is selected from trifluoromethanesulfuric acid, polyphosphoric acid or sulfuric acid.
  • reaction mass is cooled to 60-70°C, distilled out the acid under reduced pressure to get residue, which is cooled to 0-10°C, water is added to the residue followed by stirring at same temperature then the obtained solid is filtered.
  • the obtained solid is dissolved in water, resulting solution pH is adjusted to 4.0-6.0 with aqueous base to precipitate the compound and filtered to get 5-chloro-2-methyl-2, 3-dihydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one of formula IV.
  • the aqueous base used for pH adjustment is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
  • the mixture is slowly cooled to 0-10°C and the obtained solid is filtered to separate cis-isomer of formula lllb.
  • the filtrate is concentrated and alcohol solvent is added, heated to get clear solution and slowly cooled to room temperature..
  • the obtained solid is filtered to get pure trans-isomer 5- chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one of formula Ilia, wherein in alcohol solvent is selected from methanol, ethanol or isopropanol, preferably methanol.
  • Aluminium chloride is added to tetrahydrofuron solvent at 0-5°C, followed by dropwise addition of reducing agent for about 30-45min at same temperature.
  • Pure trans-isomer of formula Ilia taken in THF is slowly added to the above mixture at same temperature stirred for about 2-3hrs and filtered the salts.
  • the filtrate is concentrated to get Asenapine free base as a residue.
  • This residue is dissolved in acetone solvent, aqueous hydrobromic acid is added and stirred the mixture at room temperature for about 1hr.
  • the obtained solid is filtered to get hydrobromide salt of Asenapine of formula lla.
  • reducing agent is selected from BF3-etherate/sodium borohydride, lithium aluminium hydride (LAH)/ aluminium chloride, vitride, sodium borohydride/ aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN, preferably Aluminium chloride/ LAH
  • the unfavorable product ratio of compound of formula III can be improved by subsequent partial isomerization of the unwanted cis-isomer (lllb) into the trans- isomer (Ilia) using 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) or DBU, leading to a thermodynamic equilibrium ratio of trans-isomer (Ilia) to cis-isomer (lllb) of 3:7. Separation of the trans-isomer (Ilia) and the cis-isomer (lllb) is done by solvent purification with toluene.
  • the cis-isomer (lllb) can be isomerized again using DBN or DBU resulting in a 3:7 mixture of compound (Ilia) and compound (lllb), from which the trans-isomer (Ilia) is again separated by solvent purification.
  • Cis-isomer of 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one is taken in the mixture of toluene and 1 , 5-Diazabicyclo [4.3.0]-5-ene ( DBN) or DBU at room temperature, stir the mixture for 4-6 hours at same temperature and water is added. The pH of the solution is adjusted to 4.0-5.0 with acetic acid; the organic layer is separated and concentrated to get the residue of formula III.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising asenapine maleate and a pharmaceutically acceptable carrier, diluent or excipient, useful in the manufacture of a medicament for the treatment of schizophrenia.
  • Yet another embodiment of the present invention is to provide Asenapine maleate having the particle size d 9 o less than 100 microns, dso less than 50 microns or d 1( j less than 15 microns.
  • the present invention can be practiced using the I l-chloro-2,3-dihydro-2 -methyl- IH- dibenz[2, 3:6,7] oxepino [4,5-c] pyrrol- 1 -one compound of formula- VI, as an input material to prepare 'cis' isomer of 11-chloro-2,3 ,3 a, 12b-tetrahydro-2-methyl- 1 H-dibenz[2,3 ,6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula-VII and 'trans' isomer of 11-chloro- 2, 3,3a,12b-tetrahydro-2-methyl-IH-dibenz[2,3,6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula - VIII.
  • the present invention produces Asenapine maleate with improved yield and quality.
  • the present invention involves conversion of undesired isomer into desired isomer.
  • Example 3 Preparation of trans 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrroie-1-one of formula Ilia.
  • Toluene was distilled from the filtrate and once again repeated the above process to remove cis-isomer content (10 gm). Filtrate was distilled under reduced pressure at 45-50°C; methanol (200mL) was added to the residue and heated to 60-65°C to get clear solution. The solution was cooled to 23-30°C and stirred for 2-3 hrs. The obtained solid was filtered, washed with methanol (50m L) and dried at 40- 45°C to get pure trans-isomer of formula Ilia (10.0gm), HPLC purity >_97.0%.
  • Example 4 Recycling of 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one of formula III from cis-isomer of formula lllb.
  • Cis-isomer of formula lllb (36gm), toluene (900mL) and 1 , 5-Diazabicyclo [4.3.0]-5-ene (DBN; 5.76gm) were stirred at 23-30°C for 4 hours.
  • Water (720mL) was added, pH of the mixture was adjusted to 4.0 with acetic acid and separated toluene layer.
  • Toluene was distilled under reduced pressure to get cis, trans mixture of formula III (80gm).
  • Example 5 preparation of trans 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one hydrobromide of formula lla.
  • Aluminiumchloride (16.0gm) was added to tetrahydrofuron (1200mL) at 0-5°C under nitrogen atmosphere and stirred to get clear solution.
  • Lithiumaluminiumhydride solution (10% solution in THF) was slowly added over the period of 30-45 minutes under nitrogen atmosphere and stirred the mixture for 15 minutes at same temperature.
  • trans 11-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro- H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one of formula Ilia (100gm in lOOOmL THF) was slowly added over the period of 30-45 min and maintained stirring at 10-15 °C for 2 hours.
  • Example 6 preparation of trans 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one maleate of formula I.

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Abstract

The present invention relates to a process for the preparation of Asenapine maleate with an avoiding column chromatography by use of DBN or DBA.

Description

This application claims priority to Indian patent application number 3085/CHE/2011 filed on Sep 08, 2011.
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Asenapine maleate with an improved yield and purity without using column chromatography. -
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 frans-5-Chloro-2-methyl-2, 3, 3a, 12b- tetrahydrp- I Hdibenz [2, 3:6, 7] oxepino [4, 5-c] pyrrole (2Z)-2-butenedioate (1: 1J and having the below structure of formula I.
Figure imgf000002_0001
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 1Mb.
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-l.
Figure imgf000003_0001
II Formula I
25
Scheme-l
US patent 7872147 disclosed Asenapine process, wherein compound of formula IV is reduced in a mixture of magnesium and iodine toluene medium to get 7:3 ratios of cis and trans-isomers of compound of formula lllb and Ilia. This mixture is subjected to ring opening reaction with base to get compounds of Villa and Vlllb followed by cyclization in acid to get 2:8 ratios of cis and trans- isomers of compound of formula lllb and Ilia. This mixture is subjected to purification through column chromatography to get pure trans-isomer of formula Ilia. The complete process is shown in scheme-ll.
Figure imgf000004_0001
Scheme-ll
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 simple purification method to get the desired isomer with improved yield and quality.
SUMMARY OF THE INVENTION:
One aspect of the present invention is to provide an improved process for the preparation of Asenapine maleate comprising the steps of:
a) cyclizing the compound of formula V in the presence of strong acid to produce the compound of formula IV, b) reducing the compound of formula IV to get cis, trans mixture of formula III,
c) separating the trans-isomer of formula Ilia from step(b),
d) purifying trans-isomer of formula Ilia,
e) reducing the compound of formula Ilia, treating with aqueous hydrobromic acid to produce Asenapine hydrobromide salt of formula lis, and
f) converting the compound of formula lla to maleate salt of formula I.
According to the present invention improved process for the preparation of Asenapine maleate as shown below scheme-Ill.
Figure imgf000005_0001
ALCI3/LAH Cis and Trans (70:30)
Aq.HBr
DBN
Figure imgf000005_0002
Formula 1
Asenapine hydrobromide
Scheme-Ill
Another aspect of the present invention is to provide Asenapine maleate having the particle size of d90 less than 100 microns, dw less than 50 microns and d10 less than 15 microns.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention involves improved process for the preparation of Asenapine maleate, in which compound of formula V is subjected to cyclization in the presence of an strong acid to produce the compound of formula IV, reducing the compound of formula IV to get the cis, trans mixture of formula III, separating the trans-isomer of formula Ilia from the mixture and subjecting to reduction reaction, followed by salt formation with hydrobromic acid to get Asenapine hydrobromide of formula lla. Reacting Asenapine hydrobromide of formula Ha with maleic acid to get Asenapine maleate with improved yield and quality.
Abbreviations:
LAH lithium aluminium hydride
BBN Borabicyclo [3.3.1] nonane
DBN 1 , 5-diazabicyclo [4.3.0]-5-ene
DBU 1 , 8-Diazabicyclo [5.4.0] undec-7- BF3 Boron trifluoride
In one embodiment the present invention relates to an improved process for the preparation of Asenapine maleate which comprising the steps of:
a) cyclizing the compound of formula V in the presence of strong acid to produce the compound of formula IV,
Figure imgf000006_0001
d) purifying trans-isomer of formula Ilia, e) reducing the compound of formula Ilia, treating with aqueous hydrobromic acid to produce Asenapine hydrobromide of formula Ma and
Figure imgf000007_0001
f) converting the compound of formula HA to maleate of formula I.
Figure imgf000007_0002
II a Formula I
According to present invention 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2, 4-dione of formula V is added to strong acid and the resulting mixture heated to 100 to 130°C, preferably to 110- 115°C and maintained for 3-6 hrs at same temperature. The strong acid used in the cyclization is selected from trifluoromethanesulfuric acid, polyphosphoric acid or sulfuric acid.
After completion of the cyclization, reaction mass is cooled to 60-70°C, distilled out the acid under reduced pressure to get residue, which is cooled to 0-10°C, water is added to the residue followed by stirring at same temperature then the obtained solid is filtered. The obtained solid is dissolved in water, resulting solution pH is adjusted to 4.0-6.0 with aqueous base to precipitate the compound and filtered to get 5-chloro-2-methyl-2, 3-dihydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one of formula IV. The aqueous base used for pH adjustment is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
5-chloro-2-methyl-2, 3-dihydro-1 H-dibenzo[2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one of formula IV is dissolved in the mixture of toluene and methanol, iodine is added, followed by portion wise addition of magnesium turnings solution dissolved in methanol. The mixture is stirred for 4-8hrs at 35-45 C. Reaction mass pH is adjusted to 6.0-7.0 with aqueous hydrochloric acid; water is added and separated the toluene layer. 1 , 5-diazabicyclo [4.3.0]-5-ene (DBN) or DBU is added to the toluene layer at room temperature to increase the trans-isomer, stirred the mixture for about 3- 6hrs, water is added, followed by adjusting the pH to 3.5-4.5 with acetic acid. Toluene layer is separated and evaporated to get 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one of formula III. Compound of formula III contains 70:30 of cis, trans isomer ratio. Toluene is added to the above compound of formula III and heated to get clear solution. The mixture is slowly cooled to 0-10°C and the obtained solid is filtered to separate cis-isomer of formula lllb. The filtrate is concentrated and alcohol solvent is added, heated to get clear solution and slowly cooled to room temperature.. The obtained solid is filtered to get pure trans-isomer 5- chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one of formula Ilia, wherein in alcohol solvent is selected from methanol, ethanol or isopropanol, preferably methanol.
Aluminium chloride is added to tetrahydrofuron solvent at 0-5°C, followed by dropwise addition of reducing agent for about 30-45min at same temperature. Pure trans-isomer of formula Ilia taken in THF is slowly added to the above mixture at same temperature stirred for about 2-3hrs and filtered the salts. The filtrate is concentrated to get Asenapine free base as a residue. This residue is dissolved in acetone solvent, aqueous hydrobromic acid is added and stirred the mixture at room temperature for about 1hr. The obtained solid is filtered to get hydrobromide salt of Asenapine of formula lla. Where in reducing agent is selected from BF3-etherate/sodium borohydride, lithium aluminium hydride (LAH)/ aluminium chloride, vitride, sodium borohydride/ aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN, preferably Aluminium chloride/ LAH
The mixture of water and dichloromethane solvent is added to the Asenapine hydrobromide salt of formula lla at room temperature, adjust the pH 9.0-10.0 with aqueous sodium hydroxide solution, and stir the mixture, organic layer is concentrated to get residue. This residue is dissolved in ethanol solvent, maleic acid solution in ethanol is added at 60-65°C and stirred the reaction mass for 30-45 minutes at same temperature, the resulting solution is slowly cooled to -5 to 5°C and the obtained solid is filtered to get Asenapine maleate of formula I.
As shown in Scheme III, the unfavorable product ratio of compound of formula III can be improved by subsequent partial isomerization of the unwanted cis-isomer (lllb) into the trans- isomer (Ilia) using 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) or DBU, leading to a thermodynamic equilibrium ratio of trans-isomer (Ilia) to cis-isomer (lllb) of 3:7. Separation of the trans-isomer (Ilia) and the cis-isomer (lllb) is done by solvent purification with toluene. The cis-isomer (lllb) can be isomerized again using DBN or DBU resulting in a 3:7 mixture of compound (Ilia) and compound (lllb), from which the trans-isomer (Ilia) is again separated by solvent purification.
Recycling of cis-isomer of formula lllb
Cis-isomer of 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one is taken in the mixture of toluene and 1 , 5-Diazabicyclo [4.3.0]-5-ene ( DBN) or DBU at room temperature, stir the mixture for 4-6 hours at same temperature and water is added. The pH of the solution is adjusted to 4.0-5.0 with acetic acid; the organic layer is separated and concentrated to get the residue of formula III.
In another embodiment, the present invention provides a pharmaceutical composition comprising asenapine maleate and a pharmaceutically acceptable carrier, diluent or excipient, useful in the manufacture of a medicament for the treatment of schizophrenia.
Yet another embodiment of the present invention is to provide Asenapine maleate having the particle size d9o less than 100 microns, dso less than 50 microns or d1(j less than 15 microns.
The present invention can be practiced using the I l-chloro-2,3-dihydro-2 -methyl- IH- dibenz[2, 3:6,7] oxepino [4,5-c] pyrrol- 1 -one compound of formula- VI, as an input material to prepare 'cis' isomer of 11-chloro-2,3 ,3 a, 12b-tetrahydro-2-methyl- 1 H-dibenz[2,3 ,6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula-VII and 'trans' isomer of 11-chloro- 2, 3,3a,12b-tetrahydro-2-methyl-IH-dibenz[2,3,6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula - VIII.
Figure imgf000009_0001
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 involves single solvent in all the reaction steps, and
c) The present invention produces Asenapine maleate with improved yield and quality. d) The present invention involves conversion of undesired isomer into desired isomer.
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: Preparation of 5-chloro-2-methyl-2, 3-dihydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one of formula IV.
3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2, 4-dione of formula V (100gm) was taken in triflic acid (500mL) at 20 to 30°C, the mixture was heated to 110-115°C and maintained for 3 to 4 hours, after completion of the reaction, reaction mass temperature was cooled to 60 to 70°C and distilled out the triflic acid under reduced pressure. The obtained residue was taken / transferred in ice water at 0-10°C and the precipitated solid was filtered. This solid was suspended in water, adjusted the pH to 4.0-5.0 with 10% sodium hydroxide solution, obtained solid was filtered and dried at 60-65X to get title compound of formula IV (80gm), HPLC purity > 90.0%.
Example 2: Preparation of 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one of formula III.
11-chloro-2-methyl-2, 3-dihydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1-one of formula IV (100gm) was dissolved in 500 methanol and 500ml toluene was slowly added to the mixture of magnesium turnings (4.9gm), iodine (25.6gm) and toluene (300mL) at 40-45°C for the period of 30-40 min and maintained the reaction stirring for 5-6hrs. Magnesium turnings in seven intervals (2.8g X 7 = 19.58 gm) were added at 35-45°C. After completion of the reaction, the mixture was diluted with toluene (2Lt), pH of the solution was adjusted to 6.5-7.0 with aqueous hydrochloric acid, and the solution was further diluted with water (1Lt) and separated the toluene layer. 1 , 5- Diazabicyclo [4.3.0]-5-ene (DBN; 16ml) was added to the toluene layer, maintained stirring for 4 hours at 23-30°C and checked the cis, trans ratio formation by HPLC. Water (2Lt) was added, adjusted the pH to 4.0 with acetic acid, toluene layer was separated and evaporated under reduced pressure to get title compound of formula III (80.0gm), HPLC purity >_85.0% (cis and trans mixture).
Example 3: Preparation of trans 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrroie-1-one of formula Ilia.
11-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one of formula IV (100gm) was dissolved in toluene (200mL) at 65-70X. The mixture was slowly cooled to 23-30°C, continued the stirring for 1hr to form the slurry. Temperature was further cooled to 0-5°C, stirred for 2-3 hours; the obtained solid was filleted and dried at 40-45°C to get cis-isomer of formula IV (40gm). Toluene was distilled from the filtrate and once again repeated the above process to remove cis-isomer content (10 gm). Filtrate was distilled under reduced pressure at 45-50°C; methanol (200mL) was added to the residue and heated to 60-65°C to get clear solution. The solution was cooled to 23-30°C and stirred for 2-3 hrs. The obtained solid was filtered, washed with methanol (50m L) and dried at 40- 45°C to get pure trans-isomer of formula Ilia (10.0gm), HPLC purity >_97.0%.
Note: The cis-isomer of formula lllb was again recycled with DBN as per the example 4.
Example 4: Recycling of 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one of formula III from cis-isomer of formula lllb.
Cis-isomer of formula lllb (36gm), toluene (900mL) and 1 , 5-Diazabicyclo [4.3.0]-5-ene (DBN; 5.76gm) were stirred at 23-30°C for 4 hours. Water (720mL) was added, pH of the mixture was adjusted to 4.0 with acetic acid and separated toluene layer. Toluene was distilled under reduced pressure to get cis, trans mixture of formula III (80gm).
Example 5: preparation of trans 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one hydrobromide of formula lla.
Aluminiumchloride (16.0gm) was added to tetrahydrofuron (1200mL) at 0-5°C under nitrogen atmosphere and stirred to get clear solution. Lithiumaluminiumhydride solution (10% solution in THF) was slowly added over the period of 30-45 minutes under nitrogen atmosphere and stirred the mixture for 15 minutes at same temperature. To this mixture trans 11-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro- H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one of formula Ilia (100gm in lOOOmL THF) was slowly added over the period of 30-45 min and maintained stirring at 10-15 °C for 2 hours. After completion the reaction, the temperature was cooled to 0-5°C; saturated sodium sulphate solution (1Lt in 2Lt water) was slowly added in 30-45 minutes at 0-15°C, stirred the mixture for 15-30min at 15-25°C and filtered the salts. Toluene (500mL) was added to the filtrate, separated the organic layer and distilled under reduced pressure to get Asenapine free base as residue (80gm). Acetone (900mL) was added to the residue; aqueous hydrobromicacid (62 gm) was added and maintained the stirring 45-60 minutes at room temperature. The mixture was gradually cooled to 0-5°C and the obtained solid was filtered to get hydrobromide salt of Asenapine formula lla (100gm), HPLC purity > 99.0%.
Example 6: preparation of trans 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-1 -one maleate of formula I.
trans 5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1 H-dibenzo [2, 3:6, 7] oxepino [4, 5-c] pyrrole-lone hydrobromide of formula lla (100gm) was added to the mixture of water (1 Lt) and dichloromethane (1 Lt) at 23-30 C. The pH the mixture was adjusted to 9.5-10 with 10% sodium hydroxide solution separated the dichloromethane layer and distilled under reduced pressure to get Asenapine free base as a residue. This residue was dissolved in ethanol (100mL) and distilled under reduced pressure to remove the traces of dichloromethane. The residue was dissolved in ethanol (300mL), treated with charcoal and the solution was heated to 60-65°C. Maleic acid solution (35gm dissolved in 300mL 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 (75g), HPLC purity >99.0%.

Claims

We claim:
1. An improved process for the preparation of Asenapine maleate, which comprises : a) cyclizing the compound of formula V in the presence of strong acid to produce the compound of formula IV,
Figure imgf000013_0001
I V b) reducing th ula III,
Figure imgf000013_0002
(cts nans mixture)
c) separating the trans-isomer of formula Ilia from step (b),
Figure imgf000013_0003
d) purifying trans-isomer of formula Ilia,
e) reducing the compound of formula Ilia, treating with aqueous hydrobromic
produce Asenapine hydrobromide of formula Ha and
Figure imgf000013_0004
f) converting the compound of formula HA to maleate of formula I.
Figure imgf000014_0001
II a Formula I
The process according to claim 1 , wherein, the strong acid is selected from
trifluoromethanesulfuric acid, polyphosphoric acid or sulfuric acid.
The process according to claim 1 , wherein the reduction reagent in step b) is selected from magnesium and iodine.
The process according to claim 1 , wherein trans isomer is separated using DBN or DBU. The process according to claim 1, the reducing reagent is selected from BF3- etherate/sodium borohydride, lithium aluminium hydride (LAH)/ aluminium chloride, vitride, sodium borohydride/ aluminum chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN.
A process for the preparation of compound of formula IV, which comprising of the compound of formula V in the presence a strong acid.
Figure imgf000014_0002
The process according to claim 5, the strong acid is selected from
trifluoromethanesulfonic acid, polyphosphoric acid or sulfuric acid.
A pharmaceutical composition comprising Asenapine maleate and at least one pharmaceutically acceptable carrier.
PCT/IN2012/000591 2011-09-08 2012-09-06 Improved process for the preparation of asenapine maleate WO2013035109A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103351393A (en) * 2013-07-03 2013-10-16 华裕(无锡)制药有限公司 Reducing agent for preparing Asenapine and preparation method of Asenapine
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145434A (en) 1976-05-24 1979-03-20 Akzona Incorporated Tetracyclic derivatives and pharmaceutical compositions of matter
US20080009619A1 (en) * 2006-07-05 2008-01-10 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
US7872147B2 (en) 2005-04-07 2011-01-18 N. V. Organon Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
WO2012038975A2 (en) * 2010-09-22 2012-03-29 Msn Laboratories Limited Process for the preparation of (3ars,12brs)-5-chloro-2-methyl-2,3,3a12b-tetrahydro-1hdibenzo[2,3:6,7] oxepino [4,5-c]pyrrole maleate and it's pharmaceutical composition thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145434A (en) 1976-05-24 1979-03-20 Akzona Incorporated Tetracyclic derivatives and pharmaceutical compositions of matter
US7872147B2 (en) 2005-04-07 2011-01-18 N. V. Organon Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
US20080009619A1 (en) * 2006-07-05 2008-01-10 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
WO2012038975A2 (en) * 2010-09-22 2012-03-29 Msn Laboratories Limited Process for the preparation of (3ars,12brs)-5-chloro-2-methyl-2,3,3a12b-tetrahydro-1hdibenzo[2,3:6,7] oxepino [4,5-c]pyrrole maleate and it's pharmaceutical composition thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VADER J ET AL: "THE SYNTHESIS OF RADIOLABELLED ORG 5222 AND ITS MAIN METABOLITE ORG 30526", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, JOHN WILEY, CHICHESTER, GB, vol. 34, no. 9, 1 January 1994 (1994-01-01), pages 845 - 869, XP009071608, ISSN: 0362-4803, DOI: 10.1002/JLCR.2580340907 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103351393A (en) * 2013-07-03 2013-10-16 华裕(无锡)制药有限公司 Reducing agent for preparing Asenapine and preparation method of Asenapine
CN103351393B (en) * 2013-07-03 2016-04-06 华裕(无锡)制药有限公司 For the preparation of the reductive agent of Asenapine and the preparation method of Asenapine
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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