WO2013061247A1 - Nouveau procédé de préparation d'asénapine - Google Patents

Nouveau procédé de préparation d'asénapine Download PDF

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Publication number
WO2013061247A1
WO2013061247A1 PCT/IB2012/055824 IB2012055824W WO2013061247A1 WO 2013061247 A1 WO2013061247 A1 WO 2013061247A1 IB 2012055824 W IB2012055824 W IB 2012055824W WO 2013061247 A1 WO2013061247 A1 WO 2013061247A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
bromophenyl
methyl
oxepino
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PCT/IB2012/055824
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English (en)
Inventor
Venkatraman JAYARAMAN
Samir Patel
Samir Mistry
Bhupendra Parmar
Vishal Ray
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Alembic Pharmaceuticals Limited
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Publication of WO2013061247A1 publication Critical patent/WO2013061247A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
    • C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • 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 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.
  • 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 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 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.
  • Another object of the invention to provide novel intermediates 2-[( E )-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3 S ,4 S )-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3 S ,4 S )-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 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-[(3 S ,4 S )-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3 S ,4 S )-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)
  • 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:
  • 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-[(3 S ,4 S )-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3 S ,4 S )-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 (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-[(3 S ,4 S )-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3 S ,4 S )-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
  • 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:
  • Yet another aspect of the invention is related to the process for 2-[(3 S ,4 S )-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).
  • 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:
  • 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:
  • 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, C 1 -C 6 alcohols, or the like.
  • compounds represented by structural formulae having a pair of bold and hashed wedged bonds 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.
  • 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.
  • trans-pyrrolidine derivative 2-[(3 S ,4 S )-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).
  • 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
  • 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, CuI, 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-[(3 S ,4 S )-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 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.
  • '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 C 1 -C 4 alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof.
  • 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.
  • 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 ).
  • 2-Bromobenzyl bromide 20 gm was heated in a water bath of 80-90 o C . 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 o C in such a manner that distillation of Ethyl bromide continues. The mixture was stirred 3-4h at 120-130 o C . and further vacuum (680-700mmHg) was applied to reaction mixture to remove volatiles for 2h at 120-130 o C . The crude oil was cooled at 25-30 o C and oily product (2-Bromo-benzyl)-phosphonic acid diethyl ester was unloded and was used without further purification.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation de trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1H-dibenz[2,3:6,7]oxépino[4,5-c]pyrrole (asénapine) de formule (I). Elle concerne également de nouveaux intermédiaires, à savoir le 2-[(E)-2-(2-bromophényl)éthényl]-4-nitrophényl-acétate de formule (V), le 2-[(3S,4S)-4-(2-bromophényl)-1-méthylpyrrolidin-3-yl]-4-nitrophényl-acétate de formule (VI), le 2-[(3S,4S)-4-(2-bromophényl)-1-méthylpyrrolidin-3-yl]-4-nitrophénol de formule (VII), le 5-nitro-2-méthyl-2,3,3a,12b-tétrahydro-1H-dibenz[2,3:6,7]oxépino[4,5-c]pyrrole de formule (VIII) et le 5-amino-2-méthyl-2,3,3a,12b-tétrahydro-1H-dibenz[2,3:6,7]oxépino[4,5-c]pyrrole de formule (IX), utiles pour la préparation de sels d'asénapine de formule (I).
PCT/IB2012/055824 2011-10-24 2012-10-23 Nouveau procédé de préparation d'asénapine WO2013061247A1 (fr)

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IN3008/MUM/2011 2011-10-24

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013190481A1 (fr) * 2012-06-21 2013-12-27 Alembic Pharmaceuticals Limited Procédé pour la préparation d'asénapine et sels d'intermédiaires de celle-ci
CN104974168A (zh) * 2014-04-02 2015-10-14 洋浦慧谷医药有限公司 阿塞那平的制备方法以及用于制备阿塞那平的中间体
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
WO2021027813A1 (fr) * 2019-08-13 2021-02-18 浙江奥翔药业股份有限公司 Procédé de préparation d'asénapine
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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080009619A1 (en) * 2006-07-05 2008-01-10 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080009619A1 (en) * 2006-07-05 2008-01-10 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013190481A1 (fr) * 2012-06-21 2013-12-27 Alembic Pharmaceuticals Limited Procédé pour la préparation d'asénapine et sels d'intermédiaires de celle-ci
CN104974168A (zh) * 2014-04-02 2015-10-14 洋浦慧谷医药有限公司 阿塞那平的制备方法以及用于制备阿塞那平的中间体
CN104974168B (zh) * 2014-04-02 2019-01-04 洋浦慧谷医药有限公司 阿塞那平的制备方法以及用于制备阿塞那平的中间体
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
WO2021027813A1 (fr) * 2019-08-13 2021-02-18 浙江奥翔药业股份有限公司 Procédé de préparation d'asénapine
US11535628B2 (en) 2019-08-13 2022-12-27 Zhejiang Ausun Pharmaceutical Co., Ltd. Method for preparation of Asenapine
US11958858B2 (en) 2019-08-13 2024-04-16 Zhejiang Ausun Pharmaceutical Co., Ltd. Method for preparation of Asenapine

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