WO2017208251A1 - Nouvelle forme polymorphe stable de brexpiprazole et son procédé de préparation - Google Patents

Nouvelle forme polymorphe stable de brexpiprazole et son procédé de préparation Download PDF

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Publication number
WO2017208251A1
WO2017208251A1 PCT/IN2017/050198 IN2017050198W WO2017208251A1 WO 2017208251 A1 WO2017208251 A1 WO 2017208251A1 IN 2017050198 W IN2017050198 W IN 2017050198W WO 2017208251 A1 WO2017208251 A1 WO 2017208251A1
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WO
WIPO (PCT)
Prior art keywords
brexpiprazole
crystalline form
formula
compound
methyl
Prior art date
Application number
PCT/IN2017/050198
Other languages
English (en)
Inventor
Dharmaraj Ramachandra Rao
Geena Malhotra
Manjinder Singh Phull
Maruti Ghagare
Kanhaiyalal Nanabhau SHINDE
Manish Gopaldas Gangrade
Shashirekha Kanathala
Original Assignee
Cipla Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Limited filed Critical Cipla Limited
Publication of WO2017208251A1 publication Critical patent/WO2017208251A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a new crystalline polymorph of brexpiprazole. More specifically, the invention relates to novel Form M of brexpiprazole, process for preparing the novel form of brexpiprazole and pharmaceutical formulations comprising the novel form of brexpiprazole. The present invention also relates to an improved process for the preparation of 1-(benzo[b]thiophen-4-yl)piperazine and its further use for the preparation of brexpiprazole.
  • Brexpiprazole is a serotonin- dopamine activity modulator (SDA M) for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder and chemically known as 7-[4-(4-(Benzo[b]thien-4-yl)-piperazin-1-yl)butoxy]-1 H-quinolin-2-one.
  • SDA M serotonin- dopamine activity modulator
  • WO2013015456 discloses a dihydrate of a benzothiophene compound or a salt thereof, and a process for producing the same.
  • C N 104829603 discloses a crystalline form A of brexpiprazole hydrochloride and a process for preparing the same.
  • Polymorphism is a typical property of some molecules, wherein the occurrence of different crystal forms is noticed.
  • a single molecule may give rise to diverse polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravi metric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X -ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravi metric analysis -
  • DSC differential scanning calorimetry -
  • One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
  • Identifying new polymorphic forms and solvates of a pharmaceutical product may provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutical useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product.
  • Another object of the present invention is to provide a new stable polymorph of brexpiprazole which is suitable for use on a commercial scale.
  • Another object of the present invention is to provide an improved process for the preparation of tert-butyl 4-(benzo[b]thiophen-4-yl)piperazine-1-carboxylate.
  • Another object of the present invention is to provide an improved process for the preparation of brexpiprazole using 1-(benzo[b]thiophen-4-yl)piperazine prepared by the present invention.
  • Figure 1 X -ray diffraction spectrum of brexpiprazole Form M.
  • the present invention comprises a new stable polymorph of brexpiprazole.
  • the new polymorph of brexpiprazole is hereafter designated as ' brexpiprazole Form M _.
  • crystalline Form M characterized by having an X -ray powder diffraction pattern that comprises peaks with 2 : :values (+ 0.2) of 4.19, 8.43, 9.47, 14.62, 16.91, 18.08, 19.05, 19.80, 21.33, 22.56, 24.51, 28.30 and 30.79.
  • a second aspect of the present invention there is provided an improved process for the synthesis of 1-(benzo[b]thiophen-4-yl)piperazine or its salt (II)
  • the present invention comprises a new stable polymorph of brexpiprazole.
  • the new polymorph of brexpiprazole is hereafter designated as ' brexpiprazole Form M_.
  • the term ' stable refers to brexpiprazole Form M which does not change on storage and does not require any special conditions for storage.
  • Brexpiprazole Form M of the present invention is non- solvated crystalline form and is characterized by means of its characteristic X -ray diffraction pattern and DSC pattern.
  • crystalline Form M of brexpiprazole According to a first aspect of the present invention, there is provided crystalline Form M of brexpiprazole.
  • the crystalline Form M of the present invention have been characterized by powder X -ray diffraction spectroscopy which produces a fingerprint of the particular
  • brexpiprazole Form M in accordance with the present invention is characterized by having an X -ray powder diffraction pattern that comprises peaks with 2 : :values (+ 0.2) of 4.19, 8.43, 9.47, 14.62, 16.91, 18.08, 19.05, 19.80, 21.33, 22.56, 24.51, 28.30 and 30.79.
  • the crystalline polymorph Form M of brexpiprazole has an X RD pattern with peaks at 2 rvalues as shown in Table 1.
  • Table 1 X RD peaks of crystalline Form M of Brexpiprazole. Position d-spacing (Al) Relative
  • crystalline Form M of brexpiprazole is characterized by havi ng an X R D pattern as shown i n F igure 1.
  • crystalline Form M of brexpiprazole of the present invention is characterized as having a DSC, exhibiting a significant peak at around 184eC.
  • crystalline Form M of brexpiprazole of the present invention is characterized as having a DSC as shown in Figure 2.
  • the brexpiprazole base used in preparing the polymorph may be obtained by methods described in the prior art which are herein incorporated by reference in their entirety.
  • the brexpiprazole used as a starting material can be in any form, e.g. it can be in a reaction solution, suspension, crude or in anhydrous, hydrated or solvated form.
  • Crystalline Form M of brexpiprazole may be prepared by dissolving brexpiprazole of any form or mixture of any form in a suitable solvent or solvent mixture thereof and then precipitating crystalline Form M of brexpiprazole from the solution.
  • the suitable solvent is selected form alcohols such as methanol, ethanol, isopropyl alcohol, tert- butyl alcohol or n- butyl alcohol; ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; chlorinated solvents such as methylene di chloride, chloroform, carbon tetrachloride and ethylene di chloride; tetrahydrofuran, methyl tert-butyl ether, di isopropyl ether, toluene, xylene and a mixture thereof.
  • Preferable solvents used are mixture of alcoholic solvents and chlorinated solvents. In a most preferred embodiment the solvents used are m
  • the ratio of polar to non- polar solvent may vary from 10:1 to 1 :10, preferably 1 :10.
  • the reaction mass may be stirred for about 30 minutes to about 5 hours at a temperature of about 25eC to 80eC to get clear solution.
  • the reaction is preferably sti rred at a temperature rangi ng from about 25eC to about 50eC .
  • Precipitation can be effected by conventional means such as partial removal of solvent, lowering the temperature or by adding anti -solvent or a combination thereof.
  • seeds of brexpiprazole Form M may be used during the isolation.
  • reaction mixture containing the product was cooled down to a temperature of 5-151C.
  • anti -solvent was added followed by stirring for prolong period of time.
  • Preferable anti-solvents are n-heptane, cyclohexane, diisopropyl ether, petroleum ether and n-hexane; n-heptane being more preferable.
  • the prolonged period is from about 1 hour to about days, preferably from about 1 hour to about 1 day, more preferably from about 1 hour to about 5 hours.
  • the precipitated Form M may be isolated by filtration, for example by either gravity or
  • the precipitate may be dried at 25-60eC and/or in vacuum to obtain crystalline
  • the process of the present invention affords crystalline Form M of brexpiprazole in high purity and high yield.
  • the novel crystalline Form M of brexpiprazole obtained according to the present invention is substantially free from other crystal and non-crystal forms of brexpiprazole.
  • Substantially free_ from other forms of brexpiprazole shall be understood to mean that the polymorphs of brexpiprazole contain less than 10%, preferably less than 5%, of any other forms of brexpiprazole and less than 1 % of other impurities, water or solvates.
  • the brexpiprazole Form M prepared according to the present invention contains less than 11 % total impurities, preferably less than 6% total impurities.
  • the brexpiprazole Form M prepared according to the present invention contains less than 1 % total impurities.
  • the process of the present invention affords crystalline Form M of brexpiprazole having moisture content less than 2%.
  • novel form is environmentally friendly and suitable for use on a commercial scale.
  • the process of invention may be used as a method for purifying any form of brexpiprazole, as well as for the preparation of the new polymorphic form M.
  • the crystalline Form M of brexpiprazole obtained by the processes disclosed in the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • crystalline Form M of brexpiprazole as described above for use in medicine.
  • crystalline Form M of brexpiprazole as described above for use in treating schizophrenia, and as an adjunctive treatment for depression.
  • crystalline M of brexpiprazole as described above for use in the manufacture of a medicament for treating schizophrenia, and as an adjunctive treatment for depression.
  • a method of treating schizophrenia, and as an adjunctive treatment for depression comprising administering to a patient in need thereof a therapeutically effective amount of crystalline M of brexpiprazole as described above.
  • molar ratio of compound of formula (III) to palladium compound Tris(di benzyl ideneacetone)di pal I adium(0) is about 1 :0.01, preferably is about 1 :0.005, more preferably is about 1 :0.004.
  • molar ratio of compound of formula (III) to tertiary phosphine 2-Dicyclohexylphosphino-2 7 4 7 €-triisopropylbiphenyl is about 1 :0.02, preferably is about 1 :0.015, more preferably is about 1 :0.012.
  • inert solvent may be selected from water; ethers such as dioxane, tetrahydrofuran, diethyl ether, di ethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as DM F, DM SO, hexamethy I phosphoric tri amide, and acetonitrile.
  • a preferred inert solvent is toluene.
  • suitable base may be selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal hydrogen carbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide; and organic bases such as tri ethyl amine, tri propyl amine, pyridine, quinoline, piperidine, imidazole, N- ethyldiisopropylamine, dimethyl ami nopyri din
  • step (1) the mixture is heated to reflux temperature.
  • step (2) deprotection of the compound obtained in step (1) is carried out under acidic condition using cone HCI.
  • step (3) isolating compound (II) in form of its salt is carried out using IPA. HCI.
  • step (a) optionally purifying the compound obtained in step (a).
  • suitable base may be selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide; and organic bases such as tri ethyl amine, tri propyl amine, pyridine, quinoline, piperidine, imidazole, N- ethyldiisopropylamine, dimethyl ami
  • suitable solvent may be selected from polar solvents such as C 1-C4 alcohols; esters such as ethyl acetate; polar aprotic solvents such as sulfolane, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrol i done, dimethyl acetamide; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene di chloride, hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like
  • the dissolution temperatures may range from about 10tC to about reflux temperature of the solvent, depending on the solvent used for dissolution.
  • optionally purifying the compound obtained in step (a) may be carried out using suitable solvent may be selected from polar solvents such as C1 -C4 alcohols; esters such as ethyl acetate; polar aprotic solvents such as sulfolane, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrol i done, dimethyl acetamide; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene di chloride, hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like or mixture thereof.
  • suitable solvent may be selected from polar solvents such as C
  • the dissolution temperatures may range from about 10tC to about reflux temperature of the solvent, depending on the solvent used for dissolution.
  • Brexpiprazole (5 gm) was stirred in a mixture of M DC and methanol (10 vol, 9:1) at 20-25eC. The reaction mass was heated at 35-38eC and stirred further for 10 min. The reaction mass was allowed to cool slowly to 5-10eC. 15 volumes of n- heptane was added at 5- 10eC . T he reacti on mass was further sti rred at 5- 10eC for 2-3 Hrs. The solid was isolated by filtration, washed with n-heptane (10mL x 2) and dried under vacuum at 45-50eC for 15-18 hrs. The isolated solid was identified as crystalline Form M by powder X -ray diffraction pattern (Fig 1) and DSC (Fig 2).
  • Boc- Piperazine 131.10 gm
  • NatBuO 63.12 gm
  • the mixture was heated to reflux temperature.
  • T L C cool the mixture to 20eC to 25eC gradually and then cooled to 10eC-20eC.
  • the solid obtained was further subjected to filtration, washed with methanol (1vol) and further dried in vacuum oven at 70eC for 12 to 16 hrs. to obtain 70gm of pure brex pi praz ol e ( 53% y i el d) .

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Abstract

La présente invention concerne un nouveau polymorphe cristallin de brexpiprazole. Plus spécifiquement, l'invention concerne une nouvelle forme M de brexpiprazole, un procédé de préparation de la nouvelle forme de brexpiprazole et des formulations pharmaceutiques comprenant la nouvelle forme de brexpiprazole. La présente invention concerne également un procédé amélioré de préparation de 1-(benzo[b]thiophén-4-yl)pipérazine et son utilisation ultérieure pour la préparation de brexpiprazole.
PCT/IN2017/050198 2016-05-31 2017-05-24 Nouvelle forme polymorphe stable de brexpiprazole et son procédé de préparation WO2017208251A1 (fr)

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IN201621018652 2016-05-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909159A (zh) * 2019-05-08 2020-11-10 成都弘达药业有限公司 一种依匹哌唑有关物质及其制备方法
WO2023068253A1 (fr) * 2021-10-18 2023-04-27 大塚製薬株式会社 Nouvelle forme cristalline de composé de benzothiophène et son procédé de production

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112464A1 (fr) * 2005-04-14 2006-10-26 Otsuka Pharmaceutical Co., Ltd. Benzothiophenes a substituant piperazine pour le traitement de troubles mentaux
WO2013015456A1 (fr) * 2011-07-28 2013-01-31 Otsuka Pharmaceutical Co., Ltd. Procédé de production d'un composé benzo[b]thiophène
WO2013162046A1 (fr) * 2012-04-23 2013-10-31 Otsuka Pharmaceutical Co., Ltd. Dihydrate de composé de benzothiophène ou de sel de celui-ci, et son procédé de production
US20150086632A1 (en) * 2012-04-23 2015-03-26 Otsuka Pharmaceutical Co., Ltd. Injectable Formulation
WO2017106641A1 (fr) * 2015-12-17 2017-06-22 Assia Chemical Industries Ltd. Formes à l'état solide de brexpiprazole

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112464A1 (fr) * 2005-04-14 2006-10-26 Otsuka Pharmaceutical Co., Ltd. Benzothiophenes a substituant piperazine pour le traitement de troubles mentaux
WO2013015456A1 (fr) * 2011-07-28 2013-01-31 Otsuka Pharmaceutical Co., Ltd. Procédé de production d'un composé benzo[b]thiophène
WO2013162046A1 (fr) * 2012-04-23 2013-10-31 Otsuka Pharmaceutical Co., Ltd. Dihydrate de composé de benzothiophène ou de sel de celui-ci, et son procédé de production
US20150086632A1 (en) * 2012-04-23 2015-03-26 Otsuka Pharmaceutical Co., Ltd. Injectable Formulation
WO2017106641A1 (fr) * 2015-12-17 2017-06-22 Assia Chemical Industries Ltd. Formes à l'état solide de brexpiprazole

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909159A (zh) * 2019-05-08 2020-11-10 成都弘达药业有限公司 一种依匹哌唑有关物质及其制备方法
WO2023068253A1 (fr) * 2021-10-18 2023-04-27 大塚製薬株式会社 Nouvelle forme cristalline de composé de benzothiophène et son procédé de production

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