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WO2015081920A1 - Procédé de préparation de lurasidone et de son intermédiaire - Google Patents

Procédé de préparation de lurasidone et de son intermédiaire Download PDF

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Publication number
WO2015081920A1
WO2015081920A1 PCT/CZ2014/000148 CZ2014000148W WO2015081920A1 WO 2015081920 A1 WO2015081920 A1 WO 2015081920A1 CZ 2014000148 W CZ2014000148 W CZ 2014000148W WO 2015081920 A1 WO2015081920 A1 WO 2015081920A1
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WO
WIPO (PCT)
Prior art keywords
formula
preparation according
lurasidone
reaction
salt
Prior art date
Application number
PCT/CZ2014/000148
Other languages
English (en)
Inventor
Marketa Slavikova
Josef Hajicek
Josef Zezula
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2015081920A1 publication Critical patent/WO2015081920A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the invention relates to a new approach to the synthesis of lurasidone, the substance of chemical name (3 aR,4S,7R,7aS)-2-(((l R,2R)-2-((4-(benzo[d]isothiazol-3 -yl)piperazin- 1 - yl)methyl)cyclohexyl)methyl)hexahydro- 1 H-4,7-methanoisoindole- 1 ,3(2H)-dione of structure 1 and its salts, soli
  • Lurasidone also known as MK-3756, SM-13496, SMP-134966 is a dual antagonist of dopamine D2 and 5-HT2A receptors and is used in treating schizophrenia.
  • Lurasidone and its pharmaceutically acceptable salts were first described in EP patent 0464 846 (JP 180271/90) of Dainippon Sumitomo Pharma. Procedure of the synthesis (Scheme 1) starts from the diol of formula 4, which can be prepared by reduction of derivatives 2 or 3.
  • Optically active lurasidone can be prepared by synthesis starting from optically pure diol 4, prepared from corresponding cbiral diacid 3 by resolution (e.g. Applequist, Veraer J. Org. Chem. 1963, 28, 48).
  • the preparation and crystalline forms of the enantiomerically pure (lR,2R)-bismesyl derivative 5 are described and claimed in patent JP 2006-282527; priority March 31, 2005 (Sumitomo).
  • the invention provides a new diastereoselective procedure of preparing lurasidone, which is based on use of the new intermediate of formula 12.
  • the invention further includes a method of preparing the new intermediate of formula 12, which consists in reductive amination of the chiral intermediate of formula 1 la with the heterocyclic intermediate of formula 6.
  • the intermediate of formula 12 is subsequently diastereoisomerically purified by preparing a salt with an optically active acid.
  • Lurasidone of formula 1 can be subsequently isolated from the reaction mixture in the form of a salt with an appropriate acid to form an optically pure, which, after releasing the base, is converted to the hydrochloride or other pharmaceutically acceptable salts.
  • Stage A The Michael addition of nitromethane to 1-cyclohexene-1-carboxaldehyde runs with a high stereoselectivity (as described in WO 2011/047190 Gellman S.H.; Guo L; Giulia.no M.) in presence of a catalyst and possibly a co-catalyst with formation of two diastereoisomers 11a and 1 1 b.
  • Table no. 1 shows some experiments in various solvents.
  • the reaction can be performed under an inert atmosphere of nitrogen or argon at a temperature of 0 -35°C, preferably at 20°C, for 20-68 hours in presence of 1-18 molar % of a catalyst in various solvents, such as, for instance, alcohols, ethers, chlorinated solvents, preferably in ethanol.
  • solvents such as, for instance, alcohols, ethers, chlorinated solvents, preferably in ethanol.
  • Stage B The crude mixture of nitro aldehydes 1 la and 1 lb is reacted with the amine of formula 6 (in a ratio of 0.86 - 2.3 equivalents) in DCM at temperature -5°C to +10°C under an inert (nitrogen, argon), wherein a reducing agent is gradually added from the group of complex boron hydrides, such as NaBH(OAch or NaB ⁇ CN, preferentially NaBH(OAc) 3 (in an excess of 2.5-4.3 equivalent), and then stirred at 20°C for 16-18 hours.
  • a higher excess of amine 6 ca. more than 1.3 equivalents
  • amine 6 non-reacted during the processing is separated in high purity (HPLC 94.2%) and can be recycled.
  • the product of formula 12 can be obtained from the crude reaction mixture in the form of a salt with an optically active acid, preferably with (+)-0,0'-Di-p-toluoyl-D-tartaric acid, which provides a product with purity around 93% and with a content of the undesirable isomer of ca. 1.5-2%.
  • This salt can be easily recrystallized from methanol.
  • the salt with D-tartaric acid can also be prepared, however, in this case just a minimum improvement of diastereoisomeric purity is reached (HPLC 8H9% + 11.27% isomer).
  • Stage C For the hydrogenation of the nitro group of the intermediate of formula 12 to the amine group of the intermediate of formula 13, it is appropriate to first release the base from the salt with the optically active acid (from step B).
  • the procedure with Raney nickel in methanol in a hydrogenation autoclave has been optimized for this reaction.
  • An addition of acetic acid into the reaction mixture proved useful.
  • the reduction with hydrogen on a metal catalyst is carried out in the temperature range of 20-60°C, preferably at room temperature, and at a pressure 100 kPa to 4000 kPa, preferably 1000 kPa (10 bars).
  • the intermediate of formula 13 can be isolated from the reaction mixture, for instance, in the form of a dihydrochloride salt. Surprisingly, however, it has been found that in the next reaction step, using of the crude reaction mixture is preferred.
  • Stage D The crude reaction mixture containing the intermediate of formula 13 is dissolved in an appropriate inert organic solvent, such as, for instance, DMF, toluene, xylene; further, an organic or inorganic base (for instance TEA, DIPEA, K 2 CO3, Na 2 C0 3 ) and the anhydride of formula 14 (1.05-2.15 equivalents) can be added and the reaction mixture is heated to a temperature of 100-130°C under an inert atmosphere for 16-24 hours.
  • the product can be isolated by column chromatography or by preparation of a salt. Direct preparation of lurasidone hydrochloride has not proven well; the yield, purity and, ee (enantiomeric excess) were low.
  • the salt with D-tartaric or mandelic acid was obtained in good yields with good purity, and with ee 100%; it is prepared by the following method.
  • the evaporation residue of the crude lurasidone base is dissolved in an appropriate solvent (such as, for instance, acetone, methanol, ethanol, isopropanol) at room temperature up to boiling temperature of the solvent; a solution of an optically active acid prepared at room temperature up to boiling temperature of the solvent, preferentially in alcohol, such as methanol, ethanol, isopropanol, is added.
  • an appropriate solvent such as, for instance, acetone, methanol, ethanol, isopropanol
  • alcohol such as methanol, ethanol, isopropanol
  • An advantage of this synthesis is represented by a minimum number of purification operations for obtaining pure isolated substances with high chemical and optical purity.
  • the intermediate prepared with a high proportion (over 80%) of the desired diastereoisomer.
  • the final lurasidone has ee > 99.8% without using classical resolution of racemates with an optically active acid to form diastereoisomeric salts, which sometimes requires re-purification by repeated crystallization.
  • the preparation of salts with optically active acids serves only for isolation and for final chemical and optical purification of crude products.
  • reaction mixture is stirred at room temperature under an inert atmosphere for 24 hours.
  • the solvent is evaporated in a RVE (rotary vacuum evaporator) at the bath temperature of 40°C.
  • Ethyl acetate (100 ml) and a 0.1M aqueous solution of HCl are added to the evaporation residue, the mixture is stirred for 5 minutes, and the upper organic layer is separated.
  • the aqueous layer is shaken with ethyl acetate (30 ml).
  • the combined organic portions are washed with brine (50 ml), dried above MgSd ⁇ , and evaporated in RVE.
  • the orange oil (34.22 g; containing 21.83 g of the product; 127.5 mmol) from the previous step is dissolved in DCM (dichloromethane) (300 ml; dried, distilled), the amine of formula 6 (24.01 g; 109.5 mmol; 0.86 equivalent) is added, and the resulting solution is cooled under an inert to temperature of 0°C.
  • NaBH(OAc) 3 (67.67 g; 319.3 mmol; 2.5 equivalent) is gradually added during 15 min, the cooling is then switched off, and the reaction mixture is stirred at room temperature under an inert overnight (ca 16 hours). The excess of the agent is decomposed by a careful dropwise addition of water (30 ml) into the thick suspension.
  • the salt (13.50 g; 17.74 mmol) prepared in the previous example was stirred in DCM (100 ml), 0.5M aqueous solution of NaOH (50 ml) was added to the suspension, and the mixture was stirred intensively until dissolved (ca. 10 minutes). The organic layer was separated, the solvent evaporated in RVE.
  • the hydrogenation in methanol (200 ml) on Raney nickel (10.5 g of wet catalyst) with the addition of acetic acid (4 ml) ran at pressure of 10 bars at room temperature for 6 hours.
  • the catalyst was filtered off, the solvent evaporated in RVE, the evaporation residue dissolved in DCM (50 ml) and shaken with brine (30 ml).
  • the organic layer was separated, the solvent evaporated in RVE; a brown oil (7.14 g), HPLC 60.32%, was obtained, which corresponds to the conversion of 70.5%.
  • the crystals obtained in this way (1.59 g) can be recrystallized under boiling from methanol (70 ml).
  • the white to almost white crystals (1.12 g; 70.30% of theory) with melting point 111 - 113°C, HPLC 98.5%, ee > 99.8%, were obtained.
  • Lurasidone hydrochloride (704 mg, 1.33 mmol) is stirred in methanol (12 ml) and dissolved at 65°C. The resulting solution is left to cool down slowly. The separated crystals (492 mg, 70% of theoretical yield) are sucked off, washed with methanol (3 ml).
  • the white crystals have purity 99.83% according to HPLC, ee > 99.8%, and melting point 235 - 237.7°C

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de synthèse de lurasidone, la substance de nom chimique (3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4-(benzo [d]isothiazol-3-yl)pipérazine-1 -yl)méthyl)cyclohexyl)méthyl)-hexahydro-1H-4,7-méthanoisoindole-1,3(2H)-dione de structure 1 et ses sels. Spécifiquement, l'invention concerne un procédé de préparation diastéréosélectif de lurasidone basé sur l'utilisation du nouvel intermédiaire de formule (1)2. La réduction du groupe nitro de l'intermédiaire de formule (12) fournit l'intermédiaire de formule (13), qui réagit dans l'étape suivante avec un anhydride de formule (14) avec formation de lurasidone de formule (1), laquelle peut être davantage transformée en n'importe quel sel de lurasidone.
PCT/CZ2014/000148 2013-12-06 2014-12-05 Procédé de préparation de lurasidone et de son intermédiaire WO2015081920A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2013-977A CZ306203B6 (cs) 2013-12-06 2013-12-06 Způsob syntézy lurasidonu
CZPV2013-977 2013-12-06

Publications (1)

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WO2015081920A1 true WO2015081920A1 (fr) 2015-06-11

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CZ (1) CZ306203B6 (fr)
WO (1) WO2015081920A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016110798A1 (fr) * 2015-01-08 2016-07-14 Piramal Enterprises Limited Procédé amélioré de préparation de lurasidone et de ses intermédiaires
EP3207041B1 (fr) * 2014-10-14 2019-12-04 Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) Procédé amélioré de préparation de chlorhydrate de lurasidone

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0464846A1 (fr) 1990-07-06 1992-01-08 Sumitomo Pharmaceuticals Company, Limited Dérivés d'imides leur préparation et utilisation
WO2005009999A1 (fr) 2003-07-29 2005-02-03 Dainippon Sumitomo Pharma Co., Ltd. Procede pour produire un compose imide
JP2006282527A (ja) 2005-03-31 2006-10-19 Sumitomo Chemical Co Ltd シクロヘキサン誘導体およびその製造方法
WO2011047190A1 (fr) 2009-10-14 2011-04-21 Wisconsin Alumni Research Foundation Éléments constitutifs de gamma-aminoacides
WO2013121440A1 (fr) * 2012-02-13 2013-08-22 Cadila Healthcare Limited Procédé de préparation de benzisothiazol-3-yl-pépérazin-l-yl-méthyl-cyclohexyl-méthanisoindol-1,3-dione et de ses intermédiaires
WO2013190455A2 (fr) * 2012-06-18 2013-12-27 Shasun Pharmaceuticals Limited Procédé pour la préparation de chlorhydrate de lurasidone

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8981095B2 (en) * 2011-07-28 2015-03-17 Mapi Pharma Ltd. Intermediate compounds and process for the preparation of lurasidone and salts thereof
CN102911169B (zh) * 2011-08-02 2015-05-06 上海医药工业研究院 一种卢拉西酮的制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0464846A1 (fr) 1990-07-06 1992-01-08 Sumitomo Pharmaceuticals Company, Limited Dérivés d'imides leur préparation et utilisation
WO2005009999A1 (fr) 2003-07-29 2005-02-03 Dainippon Sumitomo Pharma Co., Ltd. Procede pour produire un compose imide
EP1652848A1 (fr) * 2003-07-29 2006-05-03 Dainippon Sumitomo Pharma Co., Ltd. Procede pour produire un compose imide
JP2006282527A (ja) 2005-03-31 2006-10-19 Sumitomo Chemical Co Ltd シクロヘキサン誘導体およびその製造方法
WO2011047190A1 (fr) 2009-10-14 2011-04-21 Wisconsin Alumni Research Foundation Éléments constitutifs de gamma-aminoacides
WO2013121440A1 (fr) * 2012-02-13 2013-08-22 Cadila Healthcare Limited Procédé de préparation de benzisothiazol-3-yl-pépérazin-l-yl-méthyl-cyclohexyl-méthanisoindol-1,3-dione et de ses intermédiaires
WO2013190455A2 (fr) * 2012-06-18 2013-12-27 Shasun Pharmaceuticals Limited Procédé pour la préparation de chlorhydrate de lurasidone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
APPLEQUIST, VERNER J. ORG. CHEM., vol. 28, 1963, pages 48

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3207041B1 (fr) * 2014-10-14 2019-12-04 Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) Procédé amélioré de préparation de chlorhydrate de lurasidone
WO2016110798A1 (fr) * 2015-01-08 2016-07-14 Piramal Enterprises Limited Procédé amélioré de préparation de lurasidone et de ses intermédiaires
US10196400B2 (en) 2015-01-08 2019-02-05 Piramal Enterprises Limited Process for the preparation of lurasidone and its intermediate

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Publication number Publication date
CZ306203B6 (cs) 2016-09-29
CZ2013977A3 (cs) 2015-06-17

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