Classifications

• • 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

Definitions

• the present invention relates to a novel process for the preparation of substantially pure trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (Asenapine) of formula (I). It also relates to novel salts of intermediates i.e.
• Asenapine exhibits potential antipsychotic activity and may be useful in the treatment of depression (see international patent application WO 99/32108).
• a pharmaceutical preparation suitable for sublingual or buccal administration of asenapine maleate has been described in the international patent application WO 95/23600 (Akzo Nobel N.V.).
• a general methodology for the preparation of asenapine is disclosed in U.S. Pat. No. 4,145,434. Physical-chemical properties of the drug substance Org 5222 have been reported (Funke et al. Arzneim. - Forsch/Drug.Res. 40, 536-539, 1990). Additional synthetic methods for the preparation of Org 5222 and radiolabelled derivatives thereof have also been described (Vader et al., J. Labelled Comp. Radiopharm. 34, 845-869, 1994).
• the yield of the acid obtained by the method is less (46%) that is not commercially viable for pharmaceutical industries.
• a generalized method for one step synthesis of methyl (monosubstituted)arylacetates from acetophenones is disclosed in Synthesis 126-127 (1981). According to this disclosure, tor example, when a mixture of acetophenone, methanol and boron trifluoride etherate is added in one lot to a stirred suspension of lead(IV) acetate in benzene at room temperature, it leads to the formation of methyl phenyl acetate in good yields.
• This process involves the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole characterised in that an E-stilbene derivative is reacted with an azomethine ylide to provide a trans-pyrrolidine derivative is treated under conditions which effect an intramolecular ring closure reaction to produce trans-5-chloro-2-methyl- 2,3 ,3a, 12b-tetrahydro- 1 H-dibenz[2,3 : 6,7] oxepino-[4,5-c]pyrrole.
• Asenapine maleate can contain process impurities, unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient (“API”) may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.
• API active pharmaceutical ingredient
• X represent salts of inorganic or organic acids selected form the group of such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis(pentafluorophenyl)boric acid, and sulfuric acid, or ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, oxalic acid, and methane sulfonic acid.
• hydrochloric acid hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, te
• Yet another object of the invention is to provide a process for the preparation of novel salts of intermediates 5-nitro-2-methyl-2,3,3a,12b-tetrahydro-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (Villa) and 5-amino-2-methyl- 2,3,3a,12b-tetrahydro-lH-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole of formula (IXa) are useful for the preparation of Asenapine of formula (I)
• An aspect of the present invention is related to process for the preparation of trans-5- chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole (Formula I) comprising:
• Another aspect of the invention is related to the invention to provide novel salts of intermediates 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-lH-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (Villa) and 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IXa) are useful for the preparation of Asenapine salts of formula (I)
• X represent salts of inorganic or organic acids selected form the group of such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis(pentafluorophenyl)boric acid, and sulfuric acid, or ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, oxalic acid, and methane sulfonic acid.
• hydrochloric acid hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, te
• Yet another aspect of the invention is related to the process for preparing novel salts of intermediates 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-lH-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole (Villa) and 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IXa).
• the maleic acid salts of 5-nitro -2-methyl -2,3 ,3a, 12b-tetrahydro- 1 H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole The hydrochloric acid salts of 5-nitro -2-methyl -2,3 ,3a, 12b-tetrahydro- 1 H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole
• the maleic acid salts of 5-amino -2-methyl- 2,3,3a,12b- tetrahydro- 1 H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole The hydrochloric acid salts of 5-amino -2-methyl- 2,3,3a,12b- tetrahydro- 1 H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole
• Yet another aspect of the invention is related to the process for Asenapine comprising steps of:
• crystallizing means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.
• treating refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating product by removal of reagents and solvents.
• trimturating refers to suspending product in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.
• acid refers of inorganic or organic acids selected form the group of such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis(pentafluorophenyl)boric acid, and sulfuric acid, or ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, oxalic acid, and methane sulfonic acid.
• an E-stilbene derivative of Formula (V) is reacted in a N-methoxymetlyl-N-trimethylsilylmethyl-N-methylamine to provide a trans-pyrrolidine derivative of Formula (VI). It is thought that the reaction proceeds in a concerted manner in which all bonds are created simultaneously. Consequently, the stereochemistry is conserved in the product. When the reaction is started with an E- stilbene derivative, the trans pyrrolidine ring is formed exclusively.
• the stereoselectivity of the dipolar addition step in the process of the invention represents a large advantage with respect to the good overall yield of the process.
• the trans-pyrrolidine derivative 2-[(35 * ,45)-4-(2- bromophenyl)-l-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII) is treated under conditions which effect an intramolecular ring closure reaction to produce trans-5-nitro- 2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole of Formula (VIII).
• the intramolecular ring closure reaction to form the 7-membered oxepine ring of asenapine can be performed with an Ullmann-type reaction, i.e. treatment of a compound of Formula (Ilia) in a solvent with copper(O) powder, with a copper(I) salt or with a copper (II) salt in the presence of a base at elevated temperatures (Ma,D., Cai,Q., Organic Letters, 5, 3799-3802, 2003; Buck, E., et. al, Organic Letters 4, 1623-1626, 202; Sawyer, J. S., Tetrahedron 5045-5065, 2002).
• Ullmann-type reaction i.e. treatment of a compound of Formula (Ilia) in a solvent with copper(O) powder, with a copper(I) salt or with a copper (II) salt in the presence of a base at elevated temperatures
• An additive such as N,N-dimethylglycine, N-methylglycine, 2,2,4,4-tetramethyl-3,5-heptanedione (TMHD) or 8-hydroxyquinoline, may be used to increase the solubility of the copper ions.
• Suitable bases include CS 2 CO 3 , K 2 CO 3 , pyridine, NaOH, KOH or CsF.
• Useful copper sources include Cu-powder, Cul, CuBr, CuCl, Cu(CO) 3 (copper(II)carbonate, Cu(OAc) 2 (copper(II)acetate), Cu(OTf) 2 (copper(II)trifluoromethanesulfonate), CU 2 O or CUSO 4 .
• Suitable conditions for complete conversion of a compound of 2-[(35 * ,45)-4-(2- bromophenyl)-l-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII) of Formula (VII) to trans-5-nitro -2-methyl-2,3,3a,12b -tetrahydro- lH-dibenz [2,3:6,7]oxepino-[4,5-c] pyrrole of Formula (VIII) are the use of Cul, ⁇ , ⁇ -dimethyl glycine and CS 2 CO 3 .
• Solvents for use in the Ullman cyclisation reaction on an industrial scale are dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), pyridine, dioxane, toluene, xylene, diethyleneglycoldimethylether (Diglyme), 2- methyltetrahydrofuran, and the like.
• Preferred reaction conditions for the Ullman cyclisation reaction at industrial scale are the use of dimethylacetamide or mixtures thereof with toluene as the solvent system, the use of CS 2 CO 3 , NaOH, KOH or K 2 CO 3 as the base, and the use of dimethylglycine in combination with copper(I)iodide as the catalyst.
• the compound of formula (VIII) which is further reacted directly, according to the invention, optionally without being isolated, using the procedure described below, to obtain the compound of formula (Villa).
• the compound of formula (VIII) is combined with solvent, preferably with halogenated hydrocarbons, or alcohols. More preferred is a solvent are such as methylene chloride, trichloroethylene or tetrachloroethylene or methanol or ethanol or propanol or isopropanol or butanol. If the resulting mixture is heated, a temperature of preferably about 25-50° C, preferably 30-40° C, particularly preferably 32-38° C is selected. Then acid is added. It is particularly preferable to use concentrated acid. Sufficient acid is added at constant temperature, with stirring, until the pH of the mixture obtained is less than 3, preferably less than 2, and particularly preferably is in the range between pH 0.6- 1.3.
• solvent preferably with halogenated hydrocarbons, or alcohols. More preferred is a solvent are such as methylene chloride, trichloroethylene or tetrachloroethylene or methanol or ethanol or propanol or isopropanol or butanol
• the mixture obtained is stirred for a further period of at least 5 to 60 min (minutes), preferably at least 10 to 45 min, particularly preferably at least 20 to 30 min.
• the solution is preferably maintained in one of the above-mentioned temperature ranges, while the temperature is particularly preferably kept constant.
• the resulting mixture is preferably cooled to a temperature in the range from 0 to 20° C, preferably 5 to 15° C, particularly preferably 7-13° C. and stirred at this temperature for a further period of at least 0.5 to 2 h (hours), preferably at least 0.75 to 1.5 h, particularly preferably at least 1 h.
• the acid used to obtain an acid addition salt of compound of formula (VIII) may be for example an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis(pentafluorophenyl)boric acid, and sulfuric acid, or with an organic acid such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, oxalic acid, and methane sulfonic acid.
• an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesul
• the resulting suspension of compound of formula (Villa) in halogenated hydrocarbons, or alcohols is then freed from the solvent by centrifuging and the residue remaining is optionally washed with one of the above-mentioned halogenated hydrocarbons, or alcohols.
• the compound of formula (Villa) obtained is then dried in vacuo at a temperature of not more than 30-65° C, preferably not more than 50-60° C.
• this salt of the compound of formula (VIII) is particularly easy to separate off, which makes it significantly simpler to isolate this intermediate product during reactions on an industrial scale.
• ease of separation is meant, within the scope of the present invention, the ability to free the resulting crystalline product from the solvent by filtration, suction filtering, centrifuging or comparable methods of isolation.
• An improvement to the separation qualities has a direct effect on the throughput of the process and is therefore of exceptional importance, particularly when carrying out reactions on an industrial scale.
• the product, having better separation qualities can be isolated faster, washed faster and better and hence dried faster as well.
• the compound of formula (IX) may be obtained from the compound of formula (Villa) using the following procedure.
• the preferred embodiment of the invention is related to the process for Asenapine wherein reducing trans-5-nitro -2-methyl -2,3,3a,12b-tetrahydro-lH-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (Villa) in the presence of reducing agent and solvent to obtain trans-5-amino -2-methyl- 2,3,3a,12b- tetrahydro- 1 H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX).
• the compound of formula (IXa) may be obtained from the compound of formula (IX) using the following procedure.
• the compound of formula (IX) is combined with solvent, preferably with halogenated hydrocarbons, or alcohols. More preferred is a solvent are such as methylene chloride, trichloroethylene or tetrachloroethylene or methanol or ethanol or propanol or isopropanol or butanol.
• solvent preferably with halogenated hydrocarbons, or alcohols. More preferred is a solvent are such as methylene chloride, trichloroethylene or tetrachloroethylene or methanol or ethanol or propanol or isopropanol or butanol.
• acid is added. It is particularly preferable to use concentrated acid. Sufficient acid is added at constant temperature, with stirring, until the pH of the mixture obtained is less than 3, preferably less than 2, and particularly preferably is in the range between pH 0.6-1.3.
• the mixture obtained is stirred for a further period of at least 5 to 60 min (minutes), preferably at least 10 to 45 min, particularly preferably at least 20 to 30 min.
• the solution is preferably maintained in one of the above-mentioned temperature ranges, while the temperature is particularly preferably kept constant.
• the resulting mixture is preferably cooled to a temperature in the range from 0 to 20° C, preferably 5 to 15° C, particularly preferably 7-13° C. and stirred at this temperature for a further period of at least 0.5 to 2 h (hours), preferably at least 0.75 to 1.5 h, particularly preferably at least 1 h.
• the acid used to obtain an acid addition salt of compound of formula (IX) may be for example an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis(pentafluorophenyl)boric acid, and sulfuric acid, or with an organic acid such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, oxalic acid, and methane sulfonic acid.
• an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesul
• the resulting suspension of compound of formula (IXa) in halogenated hydrocarbons, or alcohols is then freed from the solvent by centrifuging and the residue remaining is optionally washed with one of the above-mentioned halogenated hydrocarbons, or alcohols.
• the compound of formula (IXa) obtained is then dried in vacuo at a temperature of not more than 30-65° C, preferably not more than 50-60° C.
• the salt of the compound of formula (IXa) is particularly easy to separate off, which makes it significantly simpler to isolate this intermediate product during reactions on an industrial scale.
• ease of separation is meant, within the scope of the present invention, the ability to free the resulting crystalline product from the solvent by filtration, suction filtering, centrifuging or comparable methods of isolation.
• An improvement to the separation qualities has a direct effect on the throughput of the process and is therefore of exceptional importance, particularly when carrying out reactions on an industrial scale.
• the product, having better separation qualities can be isolated faster, washed faster and better and hence dried faster as well.
• the process or present invention is related to chlorinating trans-5 -amino -2-methyl- 2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IXa) to obtain Asenapine of formula (I).
• a "nitrile solvent” is an organic solvent containing a cyano -(C ⁇ N) bonded to another carbon atom.
• “Nitrile solvents” include, but are not limited to, tert-butyl nitrite, acetonitrile, propionitrile, C2_ 6 nitriles, or the like.
• Cupric chloride employed in the process of the present invention is made present in the reaction system by adding thereto anhydrous cupric chloride, cupric chloride dihydrate, or a material which is converted to cupric chloride in hot aqueous hydrochloric acid, for example, cupric oxide, cupric sulfate, or cupric acetate or a material which is converted to cupric chloride by chlorine in the reaction solution, for example, cuprous oxide, cuprous chloride, or cuprous acetate.
• the mixture obtained upon completion of the chlorination contains asenapine which may be isolated by ordinary isolating treatment. Asenapine may also be transformed in an acid addition salt.
• the isolated asenapine or its acid addition salt may be purified by ordinary purification means such as column chromatography or recrystallization, high vacuum distillation respectively.
• asenapine can be further purified via an acid addition salt thereof that, after being isolated and, optionally, purified is transformed again into asenapine by treatment with an organic or inorganic base.
• Asenapine isolated is combined with solvent, preferably with halogenated hydrocarbons, or alcohols. More preferred is a solvent are such as methylene chloride, trichloroethylene or tetrachloroethylene or methanol or ethanol or propanol or isopropanol or butanol and then acid is added, after the addition of the acid has ended the mixture obtained is stirred.
• the mixture obtained upon completion of the acid addition salt contains asenapine salt which may be isolated by ordinary isolating treatment.
• the salt of asenapine thus obtained is further treated with organic or inorganic base to obtain pure free base of Asenapine.
• the acid used to obtain an acid addition salt of asenapine may be for example an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis(pentafluorophenyl)boric acid, and sulfuric acid, or with an organic acid such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, oxalic acid, (-)-Diisopropyl D-tartrate, Di- 1 ,4-toluoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid, (4S,5S)-2,2-D
• Asenapine Maleate relates to process for the preparation of Asenapine Maleate.
• solvent preferably with halogenated hydrocarbons, or alcohols. More preferred is a solvent are such as methylene chloride, trichloroethylene or tetrachloroethylene or methanol or ethanol or propanol or isopropanol or butanol and then maleic acid is added, after the addition of the maleic acid has ended the mixture obtained is stirred.
• the mixture obtained upon completion of the acid addition salt contains asenapine maleate which may be isolated by ordinary isolating treatment.
• Fumaric acid (27.68 gm) was added to solution of 5-nitro -2-methyl -2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole in acetone (200ml) at 40-65°C. The mixture was stirred at 50-55°C temperature. The mixture was allowed to bring at room temperature stirred for 1 to 10 hours at room temperature. The obtained solid was than filtered, washed with isopropyl alcohol and dried.
• Example 3 Preparation of hydrochloric acid salts of 5-nitro -2-methyl -2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole Hydrochloric acid (420ml) was added to solution of 5-nitro -2-methyl -2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole in acetone (200ml) at 40-65°C. The mixture was stirred at 50-55°C temperature. The mixture was allowed to bring at room temperature stirred for 1 to 10 hours at room temperature. The obtained solid was than filtered, washed with isopropyl alcohol and dried.
• Example 4 Preparation of 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-lH-dibenz
• Example 5 Preparation of fumaric acid salts of 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole Fumaric acid (27.68 gm) was added to solution of 5-amino -2-methyl- 2,3 ,3 a, 12b- tetrahydro-lH-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole in acetone (200ml) at 40-65°C. The mixture was stirred at 50-55°C temperature. The mixture was allowed to bring at room temperature stirred for 1 to 10 hours at room temperature. The obtained solid was than filtered, washed with isopropyl alcohol and dried.
• Example 7 Preparation of Hydrochloric acid salts of 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-lH-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole Hydrochloric acid (420ml) was added to solution of 5-amino -2-methyl- 2,3,3a, 12b- tetrahydro-lH-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole in acetone (200ml) at 40-65°C. The mixture was stirred at 50-55°C temperature. The mixture was allowed to bring at room temperature stirred for 1 to 10 hours at room temperature. The obtained solid was than filtered, washed with isopropyl alcohol and dried.

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