[go: up one dir, main page]

WO2011027323A1 - Procédé de préparation de ramelteon - Google Patents

Procédé de préparation de ramelteon Download PDF

Info

Publication number
WO2011027323A1
WO2011027323A1 PCT/IB2010/053963 IB2010053963W WO2011027323A1 WO 2011027323 A1 WO2011027323 A1 WO 2011027323A1 IB 2010053963 W IB2010053963 W IB 2010053963W WO 2011027323 A1 WO2011027323 A1 WO 2011027323A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
furan
ethanamine
tetrahydro
indeno
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2010/053963
Other languages
English (en)
Inventor
Suresh Babu Jayachandra
Preeti Walia
Raghuram Morampudi
Chandra Has Khanduri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2011027323A1 publication Critical patent/WO2011027323A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a process for the preparation of ramelteon using 2- [(85 , )-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I, or a salt thereof as an intermediate.
  • Ramelteon is chemically described as N- ⁇ 2-[(SS)- 1,6,1, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethyl ⁇ propanamide, having the structure of Formula II.
  • Ramelteon is a melatonin receptor agonist with high affinity for both melatonin MTi and ⁇ 2 receptors and selectivity over the MT 3 receptor. Ramelteon acts as an oral hypnotic agent and is available in the market for the treatment of insomnia characterized by difficulty with sleep onset.
  • U.S. Patent No. 6,034,239 provides a process for the preparation of ramelteon, wherein the process involves asymmetric reduction of (2E)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III with Ru-BINAP catalyst in the presence of methanol and hydrogen gas up to 100 atmospheric pressure followed by treatment with hydrochloric acid,
  • hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I is further reacted with propionyl chloride to obtain ramelteon.
  • European Patent No. EP 1 792 899 provides an improved process for the preparation of the hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan- 8-yl]ethanamine of Formula I.
  • the process involves asymmetric reduction of (2E)-2- (l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III with Ru- BINAP catalyst in the presence of toluene and methanol under hydrogen atmosphere of 4.9 MPa; this is followed by treatment with concentrated hydrochloric acid.
  • This method subsequently employs an additional catalytic hydrogenation with palladium-carbon in the presence of sodium hydroxide to convert 2-[(8S)-7,8-dihydro-6H-indeno[5,4-b]furan-8- yl]ethanamine of Formula IA into the desired compound of Formula I.
  • European Patent No. EP 1 792 899 also employs further crystallization steps to achieve acceptable purity levels.
  • the present inventors have also observed that the hydrochloride salt of 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained by the asymmetric reduction step described in the prior art suffers from low chiral purity.
  • the present inventors have developed an advantageous process for the preparation of 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salts.
  • the present process does not require an additional reduction step with palladium- carbon as described in the prior art and at the same time provides 2-[(85')-l , 6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salts with a better purity and yield.
  • the present inventors have also found that the chiral purity of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I can be tremendously improved, without compromising the yield, by treating the hydrochloride salt of 2-[(SS)- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I with a solvent system comprising ethanol.
  • the present invention provides a simple, economic and efficient process for preparing ramelteon using 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I or its hydrochloride salt as an intermediate.
  • the present invention provides for a process for the preparation of ramelteon of Formula II.
  • the process includes:
  • step a) is carried out in the presence of a catalyst and the suitable catalyst may be a Ruthenium-, Rhodium- or Iridium-optically active phosphine complex.
  • the catalyst may be Ru 2 Cl 4 [(R)-BINAP]2N(C 2 H5)3, ⁇ RuCl(Benzene)[(R)- BINAP] ⁇ C1, ⁇ RuCl(p-Cymene) [(R)-BINAP] ⁇ C1, ⁇ RuBr(p-Cymene) [(R)-BINAP] ⁇ Br, ⁇ RuI(p-Cymene)[(R)-BINAP] ⁇ I 3 or ⁇ Rul(p-Cymene) [(R)-BINAP] ⁇ I.
  • the solvent system in step a) may include an additional organic solvent.
  • an additional organic solvent for example, a mixture of methanol and tetrahydrofuran is used as a solvent system.
  • the present invention provides for a process for the preparation of ramelteon of Formula II.
  • the process includes:
  • the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity at least 1% higher than that of the first hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I; b) optionally, converting the second hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) to a free base;
  • step a) reacting the second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) or 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained as a free base in step b) with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon; and
  • Embodiments of this aspect may include one or more of the following features.
  • the solvent system in step a) utilizes ethanol as the only solvent.
  • Step a) the process may further include dissolving the first hydrochloride salt of 2- [(85 , )-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I in the solvent system that includes ethanol, partially removing the solvent and isolating the second hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I from the mixture thereof.
  • the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity of at least about .05% more than that of the first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I.
  • a first aspect of the present invention provides a process for the preparation of ramelteon of Formula II
  • Formula III or its salt may be prepared according to the method provided in European Patent No. EP 1 792 899 or U.S. Patent No. 6,034,239. (2£)-2-(l,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-ylidene)ethanamine of Formula III or its salt is subjected to asymmetric reduction in the presence of a solvent system, which includes tetrahydrofuran and a suitable catalyst.
  • the catalyst for asymmetric reduction may be a ruthenium-, rhodium- or Iridium-optically active phosphine complex.
  • the catalyst may be, for example, Ru 2 Cl 4 [(R)-BINAP]2N(C 2 H5)3, ⁇ RuCl(Benzene)[(R)-BINAP] ⁇ Cl, ⁇ RuCl(p- Cymene) [(R)-BINAP] ⁇ C1, ⁇ RuBr(p-Cymene) [(R)-BINAP] ⁇ Br, ⁇ RuI(p-Cymene)[(R)- BINAP] ⁇ I 3 or ⁇ Rul(p-Cymene) [(R)-BINAP] ⁇ I.
  • the solvent system may additionally contain an organic solvent selected from the group consisting of alcohols, hydrocarbons, ethers, formamides and acetamides, or a mixture thereof.
  • the solvent may be, for example, a mixture of methanol and tetrahydrofuran.
  • the asymmetric reduction is carried out in a hydrogen atmosphere under pressure at a temperature of about 10°C to 100°C; for example, about 40°C to about 60°C.
  • the hydrogen pressure may be from about 1 Kg/cm to about 100 Kg/cm 2 , for example, from about 50 Kg/cm 2 to about 75 Kg/cm 2. No additional steps of catalytic reduction are needed.
  • (2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof may be isolated from the reaction mixture.
  • 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I is isolated as a hydrochloride salt by treating with
  • hydrochloric acid for example, ethanolic hydrochloric acid.
  • 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its salt is treated with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon.
  • a reactive derivative of propionic acid may be employed.
  • the reactive derivative may be a halide, amide, anhydride, active azide or an active ester of propionic acid.
  • the reactive derivate may be, for example, propionyl chloride.
  • the reaction may be carried out in the presence of a de-acidifying agent in order to remove the released hydrogen halide.
  • the de-acidifying agent may be a base selected from the group consisting of inorganic bases, tertiary amines and aromatic amines.
  • the de-acidifying agent may be, for example, triethylamine.
  • the reaction may be carried out in the presence of an organic solvent selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, formamides and acetamides.
  • the organic solvent may be, for example, dichloromethane.
  • the temperature for the reaction may be from about - 20°C to about 100°C; for example, from about 5°C to about 25°C.
  • Ramelteon may be isolated from the reaction mixture by layer separation, concentration, filtration, evaporation, decantation, solvent precipitation, or a combination thereof.
  • a second aspect of the present invention provides a process for the preparation of ramelteon of Formula II,
  • the second hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity substantially higher than that of the first hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I,
  • step b) optionally converting the second hydrochloride salt of 2-[(85')-l, 6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) to a free base,
  • step a) reacting the second hydrochloride salt of 2-[(85')- 1,6,7, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained in step a) or 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I obtained as a free base in step b) with propionic acid or its salt or its reactive derivative thereof, to obtain ramelteon; and
  • the first hydrochloride salt of 2-[(SS)- 1,6,1, 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I may be prepared according to the methods provided in U.S. Patent No. 6,034,239 or European Patent No. EP 1 792 899 or the previous aspect of the present invention.
  • the first hydrochloride salt of 2-[(85')-l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I is treated with a solvent system that includes ethanol.
  • the solvent system may contain ethanol as the only solvent.
  • the treatment with the solvent system that includes ethanol comprises the steps of dissolving the first hydrochloride salt of 2-[(SS)- 1,6,1 , 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I in the solvent system of ethanol, partially removing the solvent, specifically, for example, from about 50% to about 80% of the solvent, stirring the resultant mixture at a temperature range of from about 0° to about 25°C, and isolating the second hydrochloride salt of 2-[(SS)- 1,6,1 , 8-tetrahydro-2H-indeno[5,4-b]furan-8- yl]ethanamine of Formula I by filtration, decantation, solvent evaporation, concentration or a combination thereof.
  • the second hydrochloride salt of 2-[(SS)- 1,6,1, 8-tetrahydro-2H- indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity substantially higher than that of the first hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I.
  • the second hydrochloride salt of 2- [(85 , )-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I has a chiral purity of at least about 1% more than that of the first hydrochloride salt of 2-[(85')-l,6,7,8- tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I.
  • the second hydrochloride salt of 2-[(8S)-l,6,7,8-tetrahydro-2H-indeno[5,4- b]furan-8-yl]ethanamine of Formula I may optionally be converted into free base by treating with an organic or inorganic base.
  • the second hydrochloride salt of 2-[(85')- l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or its free base is treated with propionic acid, its salt or a reactive derivative thereof, to obtain ramelteon.
  • a reactive derivative of propionic acid may be employed.
  • the reactive derivative may be a halide, amide, anhydride, active azide or an active ester of propionic acid.
  • the reactive derivate may be, for example, propionyl chloride.
  • the reaction may be carried out in the presence of a de-acidifying agent in order to remove the released hydrogen halide.
  • the de-acidifying agent may be a base selected from the group consisting of inorganic bases, tertiary amines and aromatic amines.
  • the de-acidifying agent may be, for example, triethylamine.
  • the reaction may be carried out in the presence of an organic solvent selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, formamides and acetamides.
  • the organic solvent may be, for example, dichloromethane.
  • the temperature for the reaction may be from about -20°C to about 100°C; for example, from about 5°C to about 25°C.
  • Ramelteon may be isolated from the reaction mixture by layer separation, concentration, filtration, evaporation, decantation, solvent precipitation, or a combination thereof.
  • the catalyst was prepared by stirring a mixture of methanol (140 ml), [RuCl 2 (p-cymene)] 2 (0.74 g) and (R)-BINAP (1.49 g) at 50°C for 2 hours.) The solution was hydrogenated at 60 to 65 kg/cm at 50°C for 24 hours. The solvent was recovered under vacuum and toluene (595 ml) was added to the residue. The pH of the mixture was adjusted to 2 to 3 using ethanolic hydrochloride (10 to 12%) at 10°C to 15°C. The solid was filtered and dried under vacuum at 40°C to 45 °C to obtain the title compound. Yield: 48.03 g
  • Example 2 Purification of 2-r(8 t S')-l,6,7,8-tetrahydro-2H-Indenor5,4-blfuran-8- yllethanamine Hydrochloride: 2-[(85')-l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine hydrochloride (chemical purity 99.42% and chiral purity 98.54%; 47 g) was dissolved in ethanol (1175 ml) at 50°C to 55°C. Approximately 75% of the ethanol was recovered at 50°C to 55°C under vacuum (not less than 650 mmHg). The mixture was cooled slowly to 10°C to 15°C and stirred for 1 hour. The solid obtained was filtered, washed with cold ethanol (47 ml) and dried under vacuum at 40°C to 45 °C to obtain the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de ramelteon dans lequel on utilise du 2- [(8S)-1, 6,7, 8-tétrahydro-2H-indeno[5,4-b]furan-8-yl]éthanamine de Formule I ou un sel de ce dernier en tant qu'intermédiaire.
PCT/IB2010/053963 2009-09-03 2010-09-02 Procédé de préparation de ramelteon Ceased WO2011027323A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1821/DEL/2009 2009-09-03
IN1821DE2009 2009-09-03

Publications (1)

Publication Number Publication Date
WO2011027323A1 true WO2011027323A1 (fr) 2011-03-10

Family

ID=43082773

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/053963 Ceased WO2011027323A1 (fr) 2009-09-03 2010-09-02 Procédé de préparation de ramelteon

Country Status (1)

Country Link
WO (1) WO2011027323A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632177A (zh) * 2016-12-05 2017-05-10 万特制药(海南)有限公司 雷美替胺中间体的制备方法
CN113045524A (zh) * 2021-03-24 2021-06-29 河南牧业经济学院 一种雷美替胺中间体的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6034239A (en) 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
EP1792899A1 (fr) 2004-09-13 2007-06-06 Takeda Pharmaceutical Company Limited Procédé de fabrication de dérivés d amines optiquement actifs
WO2009093133A1 (fr) * 2008-01-25 2009-07-30 Medichem, S.A. Procédé pour déterminer la pureté énantiomérique de dérivés de l'indane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6034239A (en) 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
EP1792899A1 (fr) 2004-09-13 2007-06-06 Takeda Pharmaceutical Company Limited Procédé de fabrication de dérivés d amines optiquement actifs
WO2009093133A1 (fr) * 2008-01-25 2009-07-30 Medichem, S.A. Procédé pour déterminer la pureté énantiomérique de dérivés de l'indane

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632177A (zh) * 2016-12-05 2017-05-10 万特制药(海南)有限公司 雷美替胺中间体的制备方法
CN113045524A (zh) * 2021-03-24 2021-06-29 河南牧业经济学院 一种雷美替胺中间体的合成方法
CN113045524B (zh) * 2021-03-24 2023-09-22 河南牧业经济学院 一种雷美替胺中间体的合成方法

Similar Documents

Publication Publication Date Title
US7705184B2 (en) Method of making amphetamine
CN112851646A (zh) 特戈拉赞的制备方法
WO2003053929A1 (fr) Procede de production de derives de cis-piperidine optiquement actifs
KR100704590B1 (ko) (+)-시스-세르트랄린의 신규한 제조 방법
WO2011027323A1 (fr) Procédé de préparation de ramelteon
CN1620437A (zh) 1,7′－二甲基－2′－丙基－2,5′－双－1h－苯并咪唑的制备和纯化方法
US6635773B2 (en) Process for preparing citalopram
RU2320655C2 (ru) УЛУЧШЕННЫЙ СПОСОБ ПОЛУЧЕНИЯ α-ПОЛИМОРФНОГО БРОМГИДРАТА ЭЛЕТРИПТАНА
EP1907396B1 (fr) Procede de preparation de la 4 -amino-4'-demethyl-4-desoxypodophyllotoxine
WO2011027319A1 (fr) Procédé de préparation d'un produit intermédiaire de rameltéon
WO2014035107A1 (fr) Procédé de purification de base libre de fluvoxamine et procédé de préparation de maléate de fluvoxamine de haute pureté l'utilisant
CN120004755B (zh) 一种奥马环素的制备方法
CN1286817C (zh) 贝那普利盐酸盐的制备方法
CN1300115C (zh) 一种合成1，2，3，4－四氢异喹啉衍生物的方法
CN101704778B (zh) 一种制备4-羟基吡咯烷酮-2-乙酰胺的方法
JP4260941B2 (ja) アゼチジン−３−オール
CH616424A5 (fr)
CN106957239A (zh) 一种改进的拉科酰胺的制备方法
WO2007042848A2 (fr) Procede de preparation de carbidopa
KR100342919B1 (ko) 트랜스체 염산 트라마돌의 분리 제조방법
WO2012049646A1 (fr) Procédé de préparation d'un intermédiaire de cilazapril
CN119823170A (zh) 维贝格隆中间体化合物及其制备方法和应用
EP2417118B1 (fr) Procédé de fabrication de zéranol
WO2005021005A2 (fr) Procede pour la preparation de derives de 1,4-benzodiazepine
WO2006108910A1 (fr) Procede de cristallisation d'hydrochlorure de detomidine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10755245

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10755245

Country of ref document: EP

Kind code of ref document: A1