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.

Scheme-I

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.

Scheme-II

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).

Scheme-III

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:
f) 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;
g) compound of formula (VI) is treated with alcoholic solvent and base such as sodium hydroxide or potassium hydroxide to obtain compound of formula (VII);
h) 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);
i) compound of formula (VIII) is reduced to compound of formula (IX);
j) chlorination of compound of formula (IX) to obtain Asenapine of formula (I).

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 IIIA in a solvent with copper(0) 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  Cul  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(l)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).

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

Scheme-IV

Dated this 24th day of Oct  2011

Dr. Alpesh Pathak
Applicant’s Agent