WO2013061247A1

WO2013061247A1 - Novel process for the preparation of asenapine

Info

Publication number: WO2013061247A1
Application number: PCT/IB2012/055824
Authority: WO
Inventors: Venkatraman JAYARAMAN; Samir Patel; Samir Mistry; Bhupendra Parmar; Vishal Ray
Original assignee: Alembic Pharmaceuticals Limited
Priority date: 2011-10-24
Filing date: 2012-10-23
Publication date: 2013-05-02

Abstract

The present invention relates to a novel process 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 (Asenapine) of formula (I). It also relates to novel intermediates i.e. 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII), 5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (VIII) and 5-amino-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (IX) are useful for the preparation of Asenapine salts of formula (I).

Description

NOVEL PROCESS FOR THE PREPARATION OF ASENAPINE

FIELD OF THE INVENTION

The present invention relates to a novel process 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 (Asenapine) of formula (I). It also relates to novel intermediates i.e. 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII), 5-nitro-2-methyl -2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino [4,5-c]pyrrole of formula (VIII) and 5-amino-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (IX) are useful for the preparation of Asenapine salts of formula (I).

BACKGROUND OF THE INVENTION

Trans-5-chloro-2- methyl-2,3,3a,12b- tetrahydro-1H-dibenz[2,3:6,7] oxepino [4,5-c] -pyrrole, which is commonly known as asenapine, is a compound having CNS-depressant activity and having antihistamine and antiserotonin activities (U.S. Pat. No. 4,145,434 to van den Burg). The pharmacological profile of asenapine, its kinetics and metabolism, and the first safety and efficacy studies in human volunteers and in schizophrenic patients have been reviewed (De Boer et al., Drugs of the Future, 18(12), 1117-1123, 1993). It has been established that the maleate salt of asenapine, known as Org 5222, is a broad-spectrum, high potency serotonin, noradrenaline and dopamine antagonist.

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).

A general methodology for the preparation of asenapine is described in the US '434 patent, the disclosure of which is incorporated herein for reference. Following the generalized method given in US '434 patent, asenapine can be prepared by the method depicted in scheme-1, given below.

For preparing Asenapine from the acid (2), the carboxyl group is first transformed into the corresponding acid chloride by treatment with thionylchloride. Coupling with sarcosinemethyl ester provides for an ester (3). Treatment of the ester (3) with potassium tert-butoxide in toluene yields the cyclic dione (4), which is subjected to further ring closure to an enamide (5) by treatment with polyphosphoric acid.

The step of reducing the enamide (5) with magnesium in methanol gave a mixture of cis and trans lactam (6). Both isomers must be separated by column chromatography. It appears that the formation of the cis-lactam (6) is predominant (approx. 4:1 cis/trans). After separation, reduction of the cis or trans lactam (6) with LiAlH 4 /AlCl 3 finally furnished the cis amine (1a) or desired trans amine ( Asenapine), respectively. Because the cis isomer is predominant, the synthesis is not optimal.

It seems from the disclosure that this reaction exhibits good yields, but it also predominantly provides the unwanted cis-isomer of the compound (6a) upon subsequent work up, which leads consequently to the cis- asenapine (1a).

Additional synthetic methods for the preparation of asenapine or salts thereof are known from WO 2006/106136, WO 1998/54186 and EP 0,569,096 patent applications. Vader et al. (Labelled Comp. Radiopharm., 34(9), 845-869, 1994) discloses synthetic methods for the preparation of radiolabelled ORG 5222 and derivatives thereof. Orthorhombic crystal form of asenapine maleate is disclosed in WO 2006/106135. A method of preparation of (5-chloro-2-phenoxyphenyl) acetic acid has been disclosed by J. Med. Chem. 25, 855 (1982). The method employed is Willegerodt-Kindler reaction whose synthetic utility is seriously limited by the necessity of elevated reaction temperature and use of frequently high pressure. 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 article does not disclose preparatory methods for the phenoxyphenyl acetic acid compounds of the present invention, particularly (disubstituted)phenylacetates, more particularly (5-chloro-2-phenoxyphenyl)acetic acid or esters thereof and their further conversion to asenapine or salts thereof.

U.S. Pat. No. 7750167 discloses process for the preparation of Asenapine. This process involves the preparation of trans-5- chloro-2-methyl -2,3,3a,12b-tetrahydro-1H-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-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole.

There is a need for synthetic procedures for the preparation of asenapine which can reliably be carried out on an industrial scale.

OBJECT OF THE INVENTION

Therefore, it is an object of the invention to provide novel process 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 (Asenapine).

Another object of the invention to provide novel intermediates 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1- methylpyrrolidin -3-yl] -4-nitrophenol of formula (VII), 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (VIII) and 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX) are useful for the preparation of Asenapine salts of formula (I)

Yet another object of the invention is to provide a process for the preparation of novel intermediates 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII), 5-nitro-2- methyl-2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c]pyrrole of formula (VIII) and 5-amino-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole of formula (IX) are useful for the preparation of Asenapine salts of formula (I).

SUMMARY OF THE INVENTION

An aspect of the present invention is related to process 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 (Formula I) comprising:

a) reacting E-stilbene derivative 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V) with N-methoxymetlyl-N-trimethylsilylmethyl-N-methylamine of formula X to obtain compound of formula VI;
b) compound of formula (VI) is treated with alcoholic solvent and base such as sodium hydroxide or potassium hydroxide to obtain compound of formula (VII);
c) intermolecular ring closure of compound of formula (VII) in presence of copper or copper (I) salts or with Copper(II) salts and solvent to obtain trans-5-nitro-2- methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole compound of formula (VIII);
d) compound of formula (VIII) is reduced to compound of formula (IX);
e) chlorination of compound of formula (IX) to obtain Asenapine of formula (I).

Another aspect of the invention is related to the invention to provide novel intermediates 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII), 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (VIII) and 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX) are useful for the preparation of Asenapine salts of formula (I).

Yet another aspect of the invention is related to the process for preparing novel intermediates 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII), 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (VIII) and 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX).

Yet another aspect of the invention is related to the process for preparing novel intermediates 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V) comprising:

a) reacting 1-bromo-2-(bromomethyl)benzene of formula (II) with triphenylphosphine to obtain compound of formula (III);
b) condensation of compound of formula (III) with 2-hydroxy-5-nitrobenzaldehyde of formula (IV).

Yet another aspect of the invention is related to the process for 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI) comprises, reacting E-stilbene derivative 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V) with N-methoxymetlyl-N-trimethylsilylmethyl-N-methylamine of formula X in presences of solvent to obtain compound of formula (VI).

Yet another aspect of the invention is related to the process for 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII) comprises, treatment of 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI) with alcoholic solvent and base such as sodium hydroxide or potassium hydroxide to obtain compound of formula (VII).

Yet another aspect of the invention is related to the process trans- 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (VIII) comprises, intermolecular ring closure of compound of formula (VII) in presence of copper or copper (I) salts or with Copper(II) salts and solvent to obtain trans-5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole compound of formula (VIII).

Yet another aspect of the invention is related to the process for Asenapine comprising steps of:

a) reducing trans- 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (VIII) in the presence of reducing agent and solvent to obtain trans- 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX);
b) chlorination of trans- 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX) to obtain Asenapine of formula (I).

DETAILS DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a process 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 (Formula I) comprising:

a) reacting E-stilbene derivative 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V) with N-methoxymetly l-N-trimethylsilylmethyl-N-methylamine of formula (X) to obtain compound of formula VI;
b) compound of formula (VI) is treated with alcoholic solvent and base such as sodium hydroxide or potassium hydroxide to obtain compound of formula (VII);
c) intermolecular ring closure of compound of formula (VII) in presence of copper or copper (I) salts or with Copper(II) salts and solvent to obtain trans-5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c] pyrrole compound of formula (VIII);
d) compound of formula (VIII) is reduced to compound of formula (IX);
e) chlorination of compound of formula (IX) to obtain Asenapine of formula (I).

Throughout this disclosure 'alcoholic solvents' include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, ' 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C₁-C₆ alcohols, or the like.

Throughout this disclosure, compounds represented by structural formulae having a pair of bold and hashed wedged bonds, as shown, e.g., in the formula of compounds (I) and (VIII), refer to the 'trans' diastereoisomer. Each of the compounds may exist as a single enantiomer having the absolute stereochemical configuration indicated by the wedged bonds, or having the opposite absolute configuration, or as a mixture of enantiomers (e.g., racemate) having the relative stereochemical configuration indicated by the wedged bonds.

In a first reaction step of the process of the invention, 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.

In the second step of the process, 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI) is treated with alcoholic solvent and base such as sodium hydroxide or potassium hydroxide to obtain 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII). The trans-pyrrolidine derivative 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII) 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-1H-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 VII in a solvent with copper(II) 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). 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 Cs₂CO₃, K ₂ CO ₃ , pyridine, NaOH, KOH or CsF. Useful copper sources include Cu-powder, CuI, CuBr, CuCl, Cu(CO) ₃ (copper(II)carbonate, Cu(OAc) ₂ (copper(II)acetate), Cu(OTf) ₂ (copper(II)trifluoromethanesulfonate), Cu₂O or CuSO₄ .

Suitable conditions for complete conversion of a compound of 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII) of Formula (VII) to trans-5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole of Formula (VIII) are the use of CuI, N,N-dimethylglycine and Cs₂CO₃. 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 Cs₂CO₃, NaOH, KOH or K₂CO₃ as the base, and the use of dimethylglycine in combination with copper(I)iodide as the catalyst.

In 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-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (VIII) in the presence of reducing agent and solvent to obtain trans- 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX) and further chlorination of trans- 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX) to obtain Asenapine of formula (I).

'Reducing agent' such as metal catalyst selected from Platinum, Ruthenium, Osmium, Iridium, and especially Palladium, Raney-nickel, and sodium dithionite along with a suitable solvent chosen from water, alcohol having C₁-C₄ alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof. Preferably the reaction can favorably be conducted in the presence of palladium, charcoal and ethyl acetate. The procedure according to the present invention is also performed in a solvent mixture of ethanol and water and palladium, charcoal as catalyst this process is less costly and more advantageous.

The process for the preparation of Asenapine of formula (I) depicts below in Scheme-IV:

The following examples are illustrative and non-limiting and represent specific embodiments of the present invention.

Example 1: Preparation of N-methoxymethyl-N-trimethylsilyl-N-methylamine

A: Methyl-trimethylsilanylmethyl-amine:

A pressure flask (1000 ml) was charged with chloromethyltrimethylsilane (500 gm) and 40% aqueous methylamine. The reaction was heated to 85° C. for 3 hours, approximately 3.5-4.0 Kg pressure will develop in reaction vessel . The reaction was cooled to 10-15° C and distill out Isopropyl ether atmospherically at vapor temperature 70-73°C and the layers were separated. The product was distilled at 95-100° C unload the oil ; yielding 300 grams (75%) of methyl-trimethylsilanylmethyl-amine (the product contains 10% mol/mol Isopropyl ether ).

B: N-methoxymethyl-N-trimethylsilyl-N-methylamine:

To a cooled solution (0°C.) of formaldehyde ( 228.9 gm ) charge methanol (201 ml) drop by drop maintaining temperature -5 to 5 °C , followed by potassium carbonate (177 g), maintain the reaction mixture for 15 min at - 5 °C to 10°C. Solution of methyl- trimethylsilanylmethyl-amine (500gm) was added slowly drop by drop maintaining temperature -5 to 5 °C . After stirring for one hour the layers were separated. Charge upper layer and distill out product under vacuum at vapor temperature 25-40°C/ 30 mm Hg. (Bath temperature 60-65°C). When vapor temperature reaches to 40°C, cool the reaction mixture to 25-30°C unload the oil as product . yielding 300 grams (75%) of N-methoxymethyl-N-trimethylsilyl-N-methylamine.

Example 2: Preparation of2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V):

A: Preparation of (2-Bromo-benzyl)-phosphonic acid diethyl ester:

2-Bromobenzyl bromide ( 20 gm ) was heated in a water bath of 80-90^oC . Next triethyl phosphite ( 14.62 gm ) was added to the reaction mixture. Charge another 2-Bromobenzyl bromide (4 Lot x 20 gm) and Triethylphosphite (4 Lot x 14.62 gm) simultaneously through separate addition pots at 80-90^oC in such a manner that distillation of Ethyl bromide continues. The mixture was stirred 3-4h at 120-130^oC . and further vacuum (680-700mmHg) was applied to reaction mixture to remove volatiles for 2h at 120-130^oC . The crude oil was cooled at 25-30^oC and oily product (2-Bromo-benzyl)-phosphonic acid diethyl ester was unloded and was used without further purification.

B:Preparation of2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate:

2-hydroxy-5-nitrobenzaldehyde (100 gm ) was charged in tetrahydrofuran (1450 ml) at 25-35^oC. Next (2-bromo-benzyl)-phosphonic acid diethyl ester (202.15 gm ) was added to the reaction mixture. Further potassium tert-butoxide (180.11 gm ) was added while keeping the temperature at 25-35^oC . The reaction mass was cooled at 10-15^oC and acetic anhydride (97.74 gm) was slowly added at below 30^oC followed by flushing with tetrahydrofuran (50 ml) stir the reaction mass for about 1-2h at 25-30^oC. The pH was adjusted to pH 8 with dilute hydrochloric acid (100 ml conc. Hydrochloric acid in 400 ml DM Water) and ethyl acetate was added. The organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2X200ml). The combined organic layers were washed with water and with sodium bicarbonate solution (7.5%, 37.5 gm sodium bicarbonate in 500 ml DM Water) , sodium chloride solution (10%, 40.0 gm Sodium chloride in 400 ml DM Water) dried (MgSO₄) and then evaporated in vacuo. The resulting residue was crystallised from cyclohexane (100 ml) to give the title 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate.

Example 3: Preparation of2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol:

To a solution of 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate (100gm) in toluene (500 ml) add trifluoroacetic acid (1.0 ml) at 25-35^oC. N-methoxymetlyl-N-trimethylsilylmethyl-N-methylamine (80.16 gm ) was then added slowly through addition pot at 38-45^oC in about 1-2hr . reaction mass was stirred for about 1-2 hr at about 38-45^oC. After completion of reaction toluene was completely distilled out under vacuum. Residue was cooled and dissolved in methanol and charged with Potassium hydroxide (20.13 gm Potassium hydroxide in 100 ml DM water) slowly through addition pot at 30-35^oC reaction mass was stirred for about 1-2 hr at about 38-45^oC. The pH was adjusted to pH 8 with dilute hydrochloric acid (10%, 100ml to 150ml) and reaction mass was heated at 55-60^oC for 1h. Further the reaction mass was cooled at 20-25^oC. The resulting residue was filtered and wet cake was washed with methanol and water. The resulting residue was crystallised from methanol to give 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol.

Example 4: Preparation of5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole:

Process 1

To a mixture of 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol (100 gm) and toluene (800 ml) were added under a nitrogen atmosphere cesium carbonate (172.68 gm), N,N dimethylglycine (36.98 gm), N,N-dimethylacetamide (200 ml) and cuprous chloride (26.23 gm). The mixture was heated to reflux, stirred for 20-26 hours at reflux temperature and azeotropically reflux in dean stark column. The residue was dissolved in toluene (100 ml) and washed twice with ammonia (50 ml) and with water (50 ml). The toluene layer was dried on magnesium sulphate and evaporated.

Process 2

Potassium carbonate (6.24 g) and copper-powder (0.96g) were suspended in dimethylacetamide (25 ml). The temperature was brought to 140° C. and nitrogen was led through the suspension during 30 minutes. 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol (15 g) was then added and the reaction mixture was stirred for 29 hours. The suspension was filtered over dicalite and the solvent was evaporated. The residue was dissolved in toluene (100 ml) and washed twice with ammonia (50 ml) and with water (50 ml). The toluene layer was dried on magnesium sulphate and evaporated.

Process 3

To a solution of 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol (10 g) in methanol (100 ml) was added KOH (1.68 g). The obtained clear solution was stirred at 40° C. for 15 minutes. The solvent was evaporated, toluene (73 ml) and DMAc (18 ml) was added, followed by CuCl (1.00 g, 10 mmol), dimethylglycine (2.20 g, 21.3 mmol) and potassium carbonate (3.77 g, 27.3 mmol). After refluxing for 4 hours, the solvent was removed in vacuo. The reaction mixture was dissolved in toluene (55 ml) and extracted with 5% ammonia solution (3×55 ml). The toluene layer was dried on magnesium sulphate and evaporated.

Example 5: Preparation of5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole:

Process 1

5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole (30gm) were dissolved in 600ml methanol and phosphorous acid and 24 gm of 10gm palladium on charcoal were added. The reaction mixture was refluxed for 1 hour, cooled to room temperature and filtered over hyflo. Aqueous sodium hydroxide was added and the mixture was extracted with ethyl acetate. The crude 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole was obtained in nearly quantitative yield (268 mg, 1.0 mmol) and used without further purification.

Process 2

5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole (30gm) were dissolved in 600 ml methanol and ammonium hydroxide and 24 mg of 10gm palladium on charcoal were added. The reaction mixture was refluxed for 1 hour, cooled to room temperature and filtered over hyflo. Aqueous sodium hydroxide was added and the mixture was extracted with dichloromethane. The crude 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole was obtained in nearly quantitative yield (26.8 gm) and used without further purification.

Process 3

5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole (100gm) were dissolved in 500 ml methanol and charged 10gm of palladium on charcoal. The reaction mixture was refluxed for 1 hour, cooled to room temperature and filtered over hyflo. Aqueous sodium hydroxide was added and the mixture was extracted with dichloromethane. The crude 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole was obtained in nearly quantitative yield (26.8 gm) and used without further purification.

Example 6: Preparation of Asenapine Maleate:

5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole (35gm) were dissolved in 200ml hydrochloric acid and cooled to 0°C. 10 gm sodium nitrite (27.93gm) was added and the mixture was stirred for 30 minutes at 0°C. A few milligrams of copper chloride (66.79gm) were added and the reaction mixture was stirred for 1 hour at room temperature. Volatiles were evaporated in a stream of dry nitrogen, aqueous ammonia solution was added and the aqueous slurry was extracted with ethyl acetate and ammonia solution. The resulting product was purified with cyclohexane and ethyl acetate. Further purification is of the residue on silica gel ethyl acetate in cyclohexane (35%) afforded pure asenapine. The asenapine (100gm) was dissolved in n-propanol/ n-butyl alcohol (300ml). To this solution was added a solution of maleic acid (41.62 gram) in n-propanol. The mixture was stirred the asenapine maleate was collected and dried under vacuum at 40° C.

Claims

[1] A process for preparing trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino[4,5-c]pyrrole (Formula I)

comprising steps of:
(a) reacting E-stilbene derivative 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V);

with N-methoxymetlyl-N-trimethylsilylmethyl-N-methylamine of formula (X) to obtain compound of formula (VI);

(b) compound

subsequently treated under conditions which effect an intramolecular ring in presence of copper or copper (I) salts or with Copper(II) salts and solvent to obtain trans-5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c] pyrrole compound of formula (VIII);

(c) compound

is reduced to compound of formula (IX);

(d) chlorination of

compound of formula (IX) to obtain Asenapine of formula (I).
[2] A process for preparing novel intermediates 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V)

comprising:

(a) reacting 1-bromo-2-(bromomethyl)benzene of formula (II) with triphenylphosphine to obtain compound of formula (III);

(b) condensation of compound of formula (III) with 2-hydroxy-5-nitrobenzaldehyde of formula (IV).
[3] A process for 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI)

comprises, reacting E-stilbene derivative 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V)
with N-methoxymetlyl-N-trimethylsilylmethyl-N-methylamine of formula (X) to obtain compound of formula (VI);
[4] A process for 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII)

comprises, treatment of 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI)
with alcoholic solvent and base such as sodium hydroxide or potassium hydroxide to obtain compound of formula (VII).
[5] A process trans- 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7] oxepino [4,5-c] pyrrole of formula (VIII)

comprises, intermolecular ring closure of compound of formula (VII) in presence of copper or copper (I) salts or with Copper(II) salts and solvent to obtain trans-5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3: 6,7]oxepino-[4,5-c]pyrrole compound of formula (VIII).
[6] A process for Asenapine comprising steps of:

a) reducing trans- 5-nitro -2-methyl -2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole of formula (VIII) in the presence of reducing agent and solvent to obtain trans- 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX);

b) chlorination of trans- 5-amino -2-methyl- 2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole of formula (IX) to obtain Asenapine of formula (I).
[7] The E-stilbene-derivative 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V)
[8] The compound 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI)
[9] The compound 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII)