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WO2012046253A2 - Procédé de préparation de n-[2- (7-méthoxy-l-naphthyl) éthyl] acétamide et ses nouvelles formes cristallines - Google Patents

Procédé de préparation de n-[2- (7-méthoxy-l-naphthyl) éthyl] acétamide et ses nouvelles formes cristallines Download PDF

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WO2012046253A2
WO2012046253A2 PCT/IN2011/000699 IN2011000699W WO2012046253A2 WO 2012046253 A2 WO2012046253 A2 WO 2012046253A2 IN 2011000699 W IN2011000699 W IN 2011000699W WO 2012046253 A2 WO2012046253 A2 WO 2012046253A2
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formula
compound
methoxy
ethyl
acetamide
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WO2012046253A3 (fr
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
Karamala Rama Subba Reddy
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide represented by the structural formula- 1.
  • the present invention also provides novel crystalline forms of its intermediates as well as the final compounds.
  • N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (herein after referred as agomelatine) and process for its preparation was first disclosed in US 5225442.
  • the disclosed process involves eight steps, starting from 7-methoxy-l-tetralone.
  • the said process involves the reaction of ethyl bromo acetate, followed by aromatization and saponification to yield the corresponding acid, which is then converted to acetamide and subsequently dehydrated to yield (7-methoxy-l-naphthyl)acetonitrile, this being followed by reduction, and then condensation of the acetyl chloride.
  • agomelatine was finally recrystallized from isopropyl ether.
  • Synthetic communication 2001, 31(4), 621-629 disclosed a process for the preparation of 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile.
  • the disclosed process involves the reaction of 7-methoxy-l-tetralone with acetonitrile in the presence of n-butyl lithium. Further, the said compound obtained was purified by chromatography techniques, which is difficult to perform on a large scale. Hence there is a need to avoid chromatographic purification.
  • agomelatine was obtained as a crystalline solid from a mixture of toluene/hexane in the ratio of 2: 1 having melting range 109-110°C.
  • the PXRD of the obtained compound is shown in figure-6.
  • the said crystalline form herein is designated as Form-I.
  • the crystalline forms II, III, IV, V and VI are reported in US7498465, US7635721, US7465905, US7358395, and US20090069434A1 respectively.
  • the present invention relates to an improved process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide and novel crystalline forms of its intermediate compounds. Further, the present invention also provides a novel crystalline form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide and the process for its preparation.
  • the second aspect of the present invention is to provide a process for the preparation of (E)-2-(7-methoxy-3,4-dihydrbnaphthalen- 1 (2H)-ylidene)ethanamine compound of formula-8 and/or its acid addition salt compound of general formula-9, comprising of:
  • the third aspect of the present invention is to provide 2-(7-methoxy-3 ,4- dihydronaphthalen- l-yl)ethanamine hydrochloride salt compound of formula-6a and its crystalline form (herein designated as crystalline form-M).
  • the fifth aspect of the present invention is to provide a process for preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of aromatizing the N-(2-(7-methoxy-3 ,4-dihydronaphthalen- l-yl)ethyl)acetamide compound of formula-7 or (E)-N-(2-(7-methoxy-3 ,4-dihydronaphthalen- l(2H)-ylidene)ethyl) acetamide compound of formula- 10 with a suitable aromatizing agent in a suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.
  • the sixth aspect of the present invention is to provide a process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:
  • step-b) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl) acetamide compound of formula-7,
  • the seventh aspect of the present invention is to provide a process ⁇ £or the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:
  • step-b) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide compound of formula- 10,
  • step-c) optionally, isolating the compound obtained in step-c) from a suitable hydrocarbon or ether solvent to provide compound of formula- 10 as a solid, e) aromatizing the compound of .formula- 10 with a suitable aromatizing agent in a suitable solvent provides N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.
  • the eleventh aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 through 2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethanamine compound of formula-5 starting from 2-(l -hydroxy-7-methoxy- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4.
  • the twelfth aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 through (E)-2-(7-methoxy-3,4-dihydronaphthalen- l(2H)-ylidene)ethanamine compound of formula-8 starting from 2-(l-hydroxy-7-methoxy- 1,2,3, 4-tetrahydronaphthalen-l- yl)acetonitrile compound of formula-4.
  • the thirteenth aspect of the present invention is to provide a process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide using a suitable solvent and aqueous base.
  • the sixteenth aspect of the present invention is to provide a process for the preparation of crystalline Form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.
  • Figure-1 Illustrated the DSC thermogram of crystalline form-M of 2-(7-methoxy-3,4- dihydro naphthalen-l-yl) ethanamine hydrochloride salt compound of formula-6a.
  • Figure-2 Illustrated the DSC thermogram of crystalline form-S of (E)-2-(7-methoxy- 3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride salt compound of formula-9a.
  • Figure-3 Illustrates the PXRD of crystalline N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide oxalate compound of formula-2a.
  • Figure-4 Illustrates the PXRD of crystalline N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide hydrochloride compound of formula-2b.
  • suitable solvents are selected from “ester solvents” like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents” like tetrahydrofuran, diethylether, methyl tert-butyl ether; “hydrocarbon solvents” like toluene, hexane, heptane, pet.ether and cyclohexane; “polar aprotic solvents” like dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile; “ketone solvents” like acetone, methyethyl ketone, methyl isobutyl ketone; “alcohol solvents” like methanol, ethanol, n-propanol, isopropanol, n-butanol, diglycol and isobutanol; “chloro solvents” like dichloromethanethanediofurane, diethylether
  • base herein the present invention is selected from inorganic bases like alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert- butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and organic bases like ammonia, triethylamine, tributyl amine, dimethyl aniline, N-methyl piperidine and N-methyl pyrrolidine, N- methyl morpholine, diisopropyl methylamine, diisopropyl amine, diisopropyl ethylamine, cyclohexyldimethyl amine, piperidine, dimethyl amino pyridine, pyridine, lithium hexamethyldisilazidem (LiHMDS), sodium hexamethyldisilazide (NaHMDS) and tetraalkyl am
  • the term "acid” herein the present invention is selected from inorganic acids like hydrochloric acid and hydrobromic acid; and organic acid like acetic acid, oxalic acid.
  • aromatizing process refers to a dehydrogenating process for converting alicyclic compounds into aromatic compounds.
  • a suitable aromatizing agent is selected from a group consisting of but not limited to, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) or a proton acceptor selected from nitro alkanes or nitro arenes such as nitromethane, nitro ethane, nitro benzene and the like, optionally in the presence of a base selected from alkali metal or alkaline earth metal or tetraalkyl ammonium hydroxides, alkoxides, carbonates and bicarbonates; and a phase transfer catalyst.
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
  • a proton acceptor selected from nitro alkanes or nitro arenes such as nitromethane, nitro ethane, nitro benzene and the like
  • the first aspect of the present invention is to provide a process for the preparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 and/or its acid addition salt compound of general formula-6, comprising of:
  • Prior-art processes disclosed a two step process for the preparation of 2-(7- methoxy-3,4-dihydro naphthalen-l-yl)ethanamine compound of formula-5.
  • the present invention provides a process for preparation of compound of formula-5 in a single step, which makes the process more cost-effective and time-saving.
  • the purity of compound of formula-5 is enhanced by converting it into its hydrochloride salt compound of formula-6a, which is useful in the synthesis of highly pure N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1.
  • the present invention is more advantageous over the prior art process.
  • the second aspect of the present invention is to provide a process for the preparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine compound of formula-8 and/or its acid addition salt compound of general formula-9, comprising of:
  • the third aspect of the present invention is to provide 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a. Further, the present invention also provides the crystalline form of 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a (herein designated as crystalline form-M).
  • crystalline form-M of compound of formula-6a is characterized by its DSC thermogram showing endotherm peak at 151.12°C substantially as shown in figure- 1.
  • the fourth aspect of the present invention is to provide (E)-2-(7-methoxy-3,4- dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride salt compound of formula- 9a. Further, the present invention also provides the crystalline form of (E)-2-(7-methoxy- 3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride salt compound of formula-9a (herein designated as crystalline form-S).
  • the crystalline form-S of compound of formula-9a is characterized by its DSC thermogram showing endotherm peak at 136.87°C substantially as shown in figure-2.
  • the compounds of formula-7 and formula- 10 are important intermediates in the synthesis of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide and these have been aromatized using a suitable aromatizing agent like DDQ to provide N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1.
  • a preferred embodiment of the present invention provides N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1, which comprises of aromatizing N-(2- (7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 or (E)- N-(2-(7-methoxy-3,4-dihydro naphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula- 10 with DDQ in dichloromethane to provide N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1.
  • step-b) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl) acetamide compound of formula-7,
  • step d) optionally, isolating the compound obtained in step c) from a suitable solvent
  • step a) the suitable base used is sodium hexamethyldisilazide
  • the suitable reducing agent used is Raney-Ni or Pd-C;
  • the acid used is acetic acid;
  • the base used is ammonia;
  • the suitable solvent is selected from alcohol solvents or water or mixture thereof,
  • the suitable acetylating agent is selected from acetyl halide, acetic anhydride and acetic acid; and the suitable solvent is selected from chloro solvents and hydrocarbon solvents and ester solvents,
  • step d) isolating the compound obtained in step c) from cyclohexane to provide
  • the present invention provides a simple purification process which reduces the impurities to lower level, preferably non detectable level in HPLC.
  • the seventh aspect of the present invention is to provide N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide compound of formula- 1, comprising of:
  • step-b) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl) acetamide compound of formula- 10,
  • step d) optionally, isolating the compound obtained in step c) from a suitable solvent
  • the step b) of the present invention is carried out at a temperature below 40°C, preferably at 25-40°C, more preferably at 25-35°C.
  • the eighth aspect of the present invention is to provide a process for the purification of 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4, comprising of:
  • the suitable solvent used in step-a) is hydrocarbon solvent or mixture of hydrocarbon solvents and ester solvents in the range of 2 to 10 volumes, preferably 3 to 5 volumes to the compound of formula-4.
  • the suitable hydrocarbon solvent is selected from hexane, heptane and cyclohexane; ester solvents are selected from ethyl acetate, methyl acetate and isopropyl acetate or mixtures thereof.
  • the ninth aspect of the present invention is to provide N-(2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 as a solid and is characterized by its DSC thermogram showing endotherm peak at 107.95°C.
  • the solvent used in the step-a) of above aspect is in the range of 2 to 10 volumes, preferably 3 to 5 volumes to compound of formula-7.
  • the hydrocarbon solvent used in step-a) is selected from hexane, heptane and cyclohexane; ester solvent is selected from methyl acetate, ethyl acetate and isopropyl acetate.
  • the tenth aspect of the present invention is to provide (E)-N-(2-(7-methoxy-3,4- dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula- 10 as a crystalline solid.
  • the solvent used in step-a) of the above aspect is in the range of 2 to 10 volumes, preferably 3 to 5 volumes to compound of formula- 10.
  • the hydrocarbon solvent used is selected from hexane, heptane and cyclohexane; ether solvents are selected from tetrahydrofuran, diethylether, methyl tert-butyl ether and diisopropyl ether.
  • the eleventh aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:
  • the step a) is carried out at a temperature above 40°C, preferably at 45- 70°C, more preferably at 45-60°C.
  • the twelfth aspect of the present invention is to provide one pot process for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:
  • the step a) is carried out at a temperature below 40°C, preferably at 25- 40°C, more preferably at 25-35°C.
  • the thirteenth aspect of the present invention is to provide a process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:
  • step d) dissolving the solid obtained in step d) in a suitable solvent by heating to higher temperature
  • the aqueous base used in the above process is aqueous sodium hydroxide and the suitable solvent is polar aprotic solvent.
  • the fourteenth aspect of the present invention is to provide a process for the purification of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, comprising of:
  • the suitable solvent is selected from ester solvent, ketone solvent, hydrocarbon solvent and polar aprotic solvent,
  • step b) the acid is selected from oxalic acid, hydrochloric acid and acetic acid.
  • N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide oxalate compound of formula-2a can also be obtained in the form of co-crystals.
  • the PXRD of the said compound is depicted in figure-3.
  • the fifteenth aspect of the present invention is to provide a novel crystalline form of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide, which is characterized by its X-ray powder diffractogram having characteristic peaks at 11.20, 11.86, 19.55, 22.51 and 31.91 ⁇ 0.2 degress 2 ⁇ ; hereinafter designated as form-M.
  • the crystalline form-M of the present invention further chacterised by its PXRD peaks at 17.54, 18.38, 18.54, 19.73, 20.51, 21.78, 23.04, 24.60 and 25.39 ⁇ 0.2 degress 2 ⁇ .
  • the crystalline form may also be substantially similar to the PXRD pattern depicted in Figure-5.
  • the sixteenth aspect of the present invention is to provide a process for the preparation of crystalline form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1, which comprising of the following steps:
  • a suitable organic solvent selected from ketone solvents, ether solvents and alcoholic solvents, preferably ether solvents like methyl tertiary butyl ether,
  • reaction mixture b) heating the reaction mixture to 55° C to 80° C, preferably 65°C to 75°C and
  • the process for the preparation of novel crystalline Form-M of N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide of formula- 1 comprises of the following steps,
  • N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula- 1 obtained by the present invention is dissolved in a suitable solvent and precipitating the solid by adding water to it to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide crystalline form-I.
  • the suitable solvent used for the preparation of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide crystalline form-I is selected from DMF, DMSO, THF, acetonitrile, ketone solvents and alcohol solvents.
  • 7-methoxy-l-tetralone compound of formula-3 can be prepared by treating the anisole with succinic anhydride in the presence of acid catalyst like aluminiumtrichloride in a suitable solvent such as chloro solvents provides 4-(4- methoxyphenyl)-4-oxobutanoic acid compound of formula-11, which is reduced with a suitable reducing agent in a suitable solvent to provide 4-(4-methoxyphenyl) butanoic acid compound of formula- 12.
  • Cyclizing the compound of formula- 12 as per the known methods in the art (JP2004182660A) provided 7-methoxy-l-tetralone compound of formula-3.
  • N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Example- 1 Preparation of 2-(l-hydroxy-7methoxy-l,2,3,4-tetrahydronaphthalen-l- yl) acetonitrile (Formula-4)
  • Example-2 Purification of 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen- 1-yl) acetonitrile (Formula-4)
  • Example-3 Preparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine hydrochloride salt
  • Forma-6a 2-( 1 -hydroxy-7-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)acetonitrile compound of formula-4 (100 g) was added to a mixture of Raney-Ni (50 g), methanolic ammonia (600 ml) and water (25 ml) at 25-30°C in autoclave. Hydrogen gas (3-4 kg) was bubbled to the reaction mixture. The reaction mixture was heated to 45-55°C and then stirred for 6 hours at 45-50°C.
  • Example-5 Process for the isolation of N-(2-(7-methoxy-3,4-dihydronaphthalen-l- yl)ethyl) acetamide (Formula-7)
  • a mixture of 2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethanamine hydrochloride salt compound of formula-6a (100 g), ethylacetate (800 ml) and potassium carbonate (69.5 ml) was stirred for 15 minutes at 25-30°C and then cooled to 0-5°C.
  • Acetyl chloride (29.6 ml) was slowly added to the reaction mixture over a period of 1 hour and stirred for 1 hour at 0-5°C.
  • Example-6' Preparation of jV-l2-(7-methoxy-l-naphthyl)ethyl]acetamide(Formula-l)
  • a solution of N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 (100 g) in dichloromethane (800 ml) was cooled to 0-5°C.
  • a solution of DDQ (111.5 g) in dichloromethane (200 ml) was slowly added to the above reaction mixture at 0-5°C and then stirred for 10-20 minutes. The temperature of the reaction mixture was raised to 25-30°C and then stirred for 14 hours at same temperature.
  • Example-12 Preparation of 4-(4-methoxy phenyl) -4-oxobutanoic acid (Formula-11) Succinic anhydride (27.7 g) followed by anisole (30 g) were added to a solution of aluminium chloride (74.4 g) in dichloromethane (300 ml) at 0-5°C and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was poured into a mixture of ice water and hydrochloric acid. The reaction mixture was stirred for 2 hours at 0-5°C. Filtered the solid, washed with water and then dried to get title compound. Yield: 55 grams.
  • Example-13 Preparation of 4-(4-methoxy phenyI)butanoic acid (FormuIa-12)
  • Example-16 Purification of iV-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (Formula-1) N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (25 g) was dissolved in ethylacetate
  • N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (25 g) was dissolved in ethylacetate (50 ml) at 50-55°C.
  • a solution of oxalic acid (11.12 g) in water (50 ml) was added to the reaction mixture at 50-55°C and stirred for 30 minutes at the same temperature.
  • the reaction mixture was cooled to 0-5°C and stirred for 2 hours at the same temperature. Filtered the obtained solid, washed with water and then dried to get N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide oxalate compound of formula-2a.
  • the obtained N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide oxalate is in the form of co-crystals and its PXRD is depicted in figure-3.
  • Example-18 Preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide hydrochloride (Formula-2b) A mixture of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (25 g) and ethylacetate (50 ml) was cooled to 0-5°C and slowly added ethylacetate-hydrochloride over a period of 30 minutes until pH equals to 2. The reaction mixture was stirred for 60 minutes. Filtered the solid, washed with ethyl acetate and then dried to get N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide hydrochloride. Yield: 16 g
  • Example-22 Preparation of Form-1 of JV- [2 (7 methoxy i ⁇ naphthyl)ethyljacetamide 0.01ml of 2-(7-methoxynaphth-l-yl)etylamine is added to 6ml of pyridine. The mixture was cooled in an ice bath with stirring, and 0.012 mol of acetylchloride was added drop wise. The stirring was continued for 30minutes, and then the reaction mass was poured onto ice. The formed precipitate was washed and dried and recrystallized from Isopropyl ether. Yield: 92%

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Abstract

La présente invention concerne un procédé de préparation d'un composé de N-[2-(7-méthoxy-l-naphthyl)éthyl]acétamide de la formule 1, et des nouvelles formes cristallines de ses intermédiaires, ainsi que le composé final.
PCT/IN2011/000699 2010-10-08 2011-10-07 Procédé de préparation de n-[2- (7-méthoxy-l-naphthyl) éthyl] acétamide et ses nouvelles formes cristallines Ceased WO2012046253A2 (fr)

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IN2980/CHE/2010 2010-10-08
IN2980CH2010 2010-10-08
IN2534/CHE/2011 2011-07-25
IN2534CH2011 2011-07-25

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012097764A1 (fr) * 2011-01-21 2012-07-26 Zentiva, K.S. Formes cristallines métastables de l'agomélatine
CN102702008A (zh) * 2012-06-03 2012-10-03 上海右手医药科技开发有限公司 阿戈美拉汀硫酸复合物及其制备方法
CN102718676A (zh) * 2012-06-26 2012-10-10 福建广生堂药业股份有限公司 阿戈美拉汀硫酸盐及其制备方法
WO2012146371A1 (fr) * 2011-04-28 2012-11-01 Zentiva, K.S. Co-cristaux de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide pharmaceutiquement acceptables et leurs procédés de préparation
EP2556824A1 (fr) 2011-08-10 2013-02-13 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
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WO2014056421A1 (fr) * 2012-10-09 2014-04-17 江西同和药业有限责任公司 Composé 1-cyano-1-(7-méthoxy-1-naphtyl) méthanol ester et procédé de préparation et utilisation correspondants
EP2743255A1 (fr) 2012-12-17 2014-06-18 Dr. Reddy's Laboratories Ltd. Cocristal d'agomélatine avec de l'acide phosphorique
JP2014516921A (ja) * 2011-03-23 2014-07-17 上海医薬工業研究院 混晶アゴメラチン（ｖｉｉｉ型）、その調製方法及び使用、並びにこれを含有する医薬組成物
WO2014122405A1 (fr) 2013-02-08 2014-08-14 Les Laboratoires Servier Composition pharmaceutique solide pour l'administration buccale d'agomélatine
WO2015000555A3 (fr) * 2013-07-04 2015-03-12 Pharmathen S.A. Nouveau procédé pour la préparation de dérivés de tétraline et de naphtalène
EA021386B1 (ru) * 2011-06-09 2015-06-30 Ле Лаборатуар Сервье Новые сокристаллы агомелатина, способ их получения и фармацевтические композиции, которые их содержат
EP3075724A1 (fr) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Forme solide de l'agomélatine
WO2019011279A1 (fr) * 2017-07-12 2019-01-17 北京广为医药科技有限公司 Composé amide substitué n-(2-(naphth-1-yl substitué)éthyl), sa préparation et ses utilisations
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CN101481321B (zh) * 2009-02-27 2012-04-18 上海医药工业研究院 阿戈美拉汀卤化氢复合物及其制备方法
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WO2012097764A1 (fr) * 2011-01-21 2012-07-26 Zentiva, K.S. Formes cristallines métastables de l'agomélatine
JP2014516921A (ja) * 2011-03-23 2014-07-17 上海医薬工業研究院 混晶アゴメラチン（ｖｉｉｉ型）、その調製方法及び使用、並びにこれを含有する医薬組成物
US8927771B2 (en) 2011-04-28 2015-01-06 Zentiva K.S. Pharmaceutically acceptable cocrystals of N-[2-(7-methoxyl-1-naphtyl)ethyl]acetamide and methods of their preparation
WO2012146371A1 (fr) * 2011-04-28 2012-11-01 Zentiva, K.S. Co-cristaux de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide pharmaceutiquement acceptables et leurs procédés de préparation
EA024422B1 (ru) * 2011-04-28 2016-09-30 Зентива, К.С. Фармацевтически приемлемые сокристаллы n-[2-(7-метокси-1-нафтил)этил]ацетамида и способы их получения
EA021386B1 (ru) * 2011-06-09 2015-06-30 Ле Лаборатуар Сервье Новые сокристаллы агомелатина, способ их получения и фармацевтические композиции, которые их содержат
EP2532647B1 (fr) * 2011-06-09 2016-09-28 Les Laboratoires Servier Nouveaux co-cristaux d'agomelatin.
WO2013021139A1 (fr) 2011-08-10 2013-02-14 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
EP2556824A1 (fr) 2011-08-10 2013-02-13 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
CN102702008A (zh) * 2012-06-03 2012-10-03 上海右手医药科技开发有限公司 阿戈美拉汀硫酸复合物及其制备方法
CN102718676A (zh) * 2012-06-26 2012-10-10 福建广生堂药业股份有限公司 阿戈美拉汀硫酸盐及其制备方法
EP2703383A1 (fr) 2012-08-27 2014-03-05 Procos S.p.A. Procédé de préparation dýagomélatine
WO2014056421A1 (fr) * 2012-10-09 2014-04-17 江西同和药业有限责任公司 Composé 1-cyano-1-(7-méthoxy-1-naphtyl) méthanol ester et procédé de préparation et utilisation correspondants
EP2743255A1 (fr) 2012-12-17 2014-06-18 Dr. Reddy's Laboratories Ltd. Cocristal d'agomélatine avec de l'acide phosphorique
WO2014122405A1 (fr) 2013-02-08 2014-08-14 Les Laboratoires Servier Composition pharmaceutique solide pour l'administration buccale d'agomélatine
WO2015000555A3 (fr) * 2013-07-04 2015-03-12 Pharmathen S.A. Nouveau procédé pour la préparation de dérivés de tétraline et de naphtalène
EP3075724A1 (fr) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Forme solide de l'agomélatine
WO2019011279A1 (fr) * 2017-07-12 2019-01-17 北京广为医药科技有限公司 Composé amide substitué n-(2-(naphth-1-yl substitué)éthyl), sa préparation et ses utilisations
CN109476584A (zh) * 2017-07-12 2019-03-15 北京广为医药科技有限公司 N-(2-(取代-萘-1-基)乙基)取代酰胺类化合物、其制备及其用途
CN109476584B (zh) * 2017-07-12 2019-10-25 北京广为医药科技有限公司 N-(2-(取代-萘-1-基)乙基)取代酰胺类化合物、其制备及其用途
JP2020528451A (ja) * 2017-07-12 2020-09-24 北京广▲為▼医▲薬▼科技有限公司 Ｎ−（２−（置換ナフタレン−１−イル）エチル）置換アミド系化合物、その調製および使用
US11980598B2 (en) 2017-07-12 2024-05-14 Beijing Greatway Pharmaceutical Technology Co., Ltd. N-(2-(substituted-naphth-1-yl)ethyl) substituted amide compound, preparation and uses thereof
CN111807968A (zh) * 2020-07-01 2020-10-23 复旦大学 一种2-（1-环己烯基）乙胺的合成方法
CN111807968B (zh) * 2020-07-01 2022-05-20 复旦大学 一种2-(1-环己烯基)乙胺的合成方法

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