EP3452462A1 - Formes à l'état solide d'acide 2-[4-(2-{4-[1-(2-éthoxyéthyl)-1h-benzimidazol-2-yl]-1-pipéridinyl}éthyl)phényl]-2-méthylpropanoïque et procédé de préparation associé - Google Patents

Formes à l'état solide d'acide 2-[4-(2-{4-[1-(2-éthoxyéthyl)-1h-benzimidazol-2-yl]-1-pipéridinyl}éthyl)phényl]-2-méthylpropanoïque et procédé de préparation associé

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Publication number
EP3452462A1
EP3452462A1 EP17792622.7A EP17792622A EP3452462A1 EP 3452462 A1 EP3452462 A1 EP 3452462A1 EP 17792622 A EP17792622 A EP 17792622A EP 3452462 A1 EP3452462 A1 EP 3452462A1
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Prior art keywords
compound
formula
solvents
solvent
reaction mixture
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EP17792622.7A
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German (de)
English (en)
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EP3452462A4 (fr
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
Sagyam RAJESHWAR REDDY
Singavarapu ADILAKSHMI
Boge RAJESHAM
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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Publication of EP3452462A1 publication Critical patent/EP3452462A1/fr
Publication of EP3452462A4 publication Critical patent/EP3452462A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention provides solid state forms of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)- 1 H- benzimidazot-2-yl]-l -piperidinyl ⁇ ethyl)pheny!]-2-methylpropanoic acid represented by the following structural formul - 1 and process for preparation thereof.
  • the present inventors were able to prepare new solid state forms of 2-[4-(2- ⁇ 4-[l -(2- ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 -piperidiny 1 ⁇ ethy l)pheny l]-2-methy Ipropanoic acid, which are useful for the preparation of various pharmaceutical compositions.
  • the first aspect of the present invention is to provide pure amorphous form of 2-[4- (2- ⁇ 4-[l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]-l -piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula-1.
  • the second aspect of the present invention is to provide a process for the preparation of pure amorphous form of 2-[4-(2- ⁇ 4-[l -(2-ethoxyethyl)-l H-benzimidazol-2-yl]-l - piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1.
  • the third aspect of the present invention is to provide amorphous solid dispersion comprising 2-[4-(2- ⁇ 4-[ 1 -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 -piperidinyl ⁇ ethyl) phenyl]-2-methylpropanoic acid compound of formula- 1 and at least one pharmaceutically acceptable excipient.
  • the fourth aspect of the present invention is to a provide process for the preparation of amorphous solid dispersion comprising 2-[4-(2- ⁇ 4-[l -(2-ethoxyethyl)-l H-benzimidazol-2- yl]-l -piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid compound of formula-1 and at least one pharmaceutically acceptable excipient.
  • the fifth aspect of the present invention is to provide a process for the preparation of crystalline form-2 of 2-[4-(2- ⁇ 4-[l -(2-ethoxyethyl)- lH-benzimidazol-2-yl]-l -piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid compound of formula- 1 .
  • the sixth aspect of the present invention is to provide another process for the preparation of crystalline form-2 of 2-[4-(2- ⁇ 4-[l -(2-ethoxyethyl)-l H-benzimidazol-2-yl]- l - piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid compound of formula-1 .
  • Figure-1 Illustrates the PXRD pattern of compound of formula-1 obtained according to example- 1
  • Figure-2 Illustrates the PXRD pattern of crystalline form-M of compound of formula-1
  • Figure-3 Illustrates the PXRD pattern of pure amorphous form of compound of formula- 1
  • Figure-4 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and Povidone K-30
  • Figure-5 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- 1 and hydroxypropyl cellulose (HPC)
  • Figure-6 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- 1 and hydroxypropyl methyl cellulose (HPMC)
  • Figure-7 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- 1 and hydroxypropyl methyl cellulose acetate succinate (HPMC AS)
  • Figure-8 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and Eudragit.
  • suitable solvent refers to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1 ,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethyls
  • the first aspect of the present invention provides pure amorphous form of 2-[4-(2- ⁇ 4- [ 1 -(2-ethoxyethy I)- 1 H-benzimidazol-2-y I]- 1 -piperidiny 1 ⁇ ethyl)phenyl]-2-methy Ipropanoic acid compound of formula- 1 .
  • the pure amorphous form of compound of formula- 1 of the present invention is characterized by its PXRD pattern as illustrated in figure-3.
  • An embodiment of the present invention provides a process for the preparation of pure amorphous form of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1 , comprising of;
  • the suitable solvent is selected from alcohol solvents, chloro solvents, polar-aprotic solvents or their mixtures; and the suitable temperature ranges from 25°C to reflux temperature of the solvent used.
  • the second aspect of the present invention provides a process for the preparation of pure amorphous form of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1 , comprising of;
  • the suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction or by any other suitable techniques known in the art.
  • the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution and the solution may optionally be filtered to make it particle free.
  • a preferred embodiment of the present invention provides a process for the preparation of pure amorphous form of compound of formula- 1 , comprising of;
  • the third aspect of the present invention provides amorphous solid dispersion comprising 2-[4-(2- ⁇ 4-[ 1 -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 -piperidiny 1 ⁇ ethyl) phenyl]-2-methylpropanoic acid compound of formula- 1 and at least one pharmaceutically acceptable excipient.
  • solid dispersion means any solid composition having at least two components, in certain embodiments, a solid dispersion as disclosed herein includes an active ingredient (compound of formula- 1 ) dispersed among at least one other component, for example an excipient.
  • the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K- 1 5, K-30, K-60, K-90 and K- 120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthatate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl methyl
  • the excipient selected from povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, Eudragit.
  • the pure amorphous form as well as amorphous solid dispersion of compound of formula- 1 of the present invention are having purity of greater than 98%, preferably greater than 99% by HPLC and is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition in particular polymorphic form mentioned.
  • Such pharmaceutical compositions may comprise compound of formula- 1 present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
  • additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
  • the amorphous solid dispersion of the present invention is stable at room temperature under normal stability conditions and does not convert to any other solid state form.
  • An embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising compound of formula- 1 and at least one pharmaceutically acceptable excipient, comprising of;
  • the suitable solvent is selected from but not limited to alcohol solvents, chloro solvents, polar-aprotic solvents or their mixtures; and the suitable temperature ranges from 25°C to reflux temperature of the solvent used.
  • the fourth aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising 2-[4-(2- ⁇ 4-[ I -(2-ethoxyethyl)- l H-benzimidazol-2- yl]-l -piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid compound of formula- 1 and at least one pharmaceutically acceptable excipient, comprising of;
  • step-a) the excipient is same as defined above in the third aspect;
  • the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution and the solution may optionally be filtered to make it particle free.
  • the suitable technique which may be used for the removal of the solvent from the reaction mixture and the conditions under which the solvent can be removed are same as defined in the second aspect of the present invention.
  • the suitable techniques may also include vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor.
  • filtering the reaction mixture/solution to make it particle free can be carried out by passing through paper, cloth, glass fiber or other membrane material or a bed of a clarifying agent such as Celite® or hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • the ratio of the amount by weight of compound of formula- 1 within the solid dispersion to the amount by weight of the excipient therein ranges from but not limited to about 1 :0.05 to about 1 :5.
  • a preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising compound of formula- 1 and at least one excipient, comprising of;
  • An embodiment of the present invention provides a process for the preparation of crystalline form-2 of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid compound of formula- ! , comprising of;
  • the suitable solvent is selected from alcohol solvents, chloro solvents, polar-aprotic solvents or their mixtures;
  • the suitable second solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, ketone solvents, nitrile solvents, polar solvents or their mixtures; and the suitable temperature ranges from -40°C to 40°C.
  • the fifth aspect of the present invention provides a process for the preparation of crystalline form-2 of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid compound of formula- 1 , comprising of;
  • step-a) the dissolution can be carried out at 20-35°C;
  • step-c) the compound can be slurried in cyclohexane at a suitable temperature ranges from -30°C to 40°C.
  • An embodiment of the present invention provides a process for the preparation of crystalline form-2 of compound of formula- 1 , comprising of;
  • the suitable solvent is selected from but not limited to alcohol solvents, chloro solvents, polar-aprotic solvents or their mixtures; and the suitable temperature ranges from 25°C to reflux temperature of the solvent used;
  • the suitable anti-solvent is selected from but not limited to polar solvents, hydrocarbon solvents, ether solvents, ketone solvents, ester solvents, nitrile solvents or their mixtures; and the suitable temperature ranges from -70°C to 40°C;
  • the suitable solvent is selected from but not limited to polar solvents, hydrocarbon solvents, ether solvents, ketone solvents, ester solvents, nitrile solvents or their mixtures; and the suitable temperature ranges from -70°C to 40°C.
  • a small amount of crystalline form-2 can be added as seeding material either to the solution of step-a) or step-b) or to the anti-solvent in order to facilitate the formation of crystalline form-2 as product.
  • the sixth aspect of the present invention provides a process for the preparation of crystalline form-2 of 2-[4-(2- ⁇ 4-[l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid compound of formula- 1 , comprising of;
  • step-a) the dissolution can be carried out at 20-35°C;
  • step-b) the suitable temperature ranges from -30°C to 30°C, preferably 0-5°C;
  • step-d) the suitable temperature ranges from -30°C to 30°C.
  • An embodiment of the present invention provides a process for the preparation of crystalline form-2 of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethy])- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyt)phenyl]-2-methylpropanoic acid compound of formuta-1 , comprising of adding a small amount of crystalline form-2 to the reaction mixture as seed material.
  • the processes for the preparation of crystal line form-2 of compound of formula- 1 developed by the present inventors is efficient and produces the product with high yield and polymorphic purity as well as with greater stability.
  • An embodiment of the present invention provides crystalline polymorph of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)-l H-benzimidazol-2-yl]-l -piperidinyi ⁇ ethyi)phenyl]-2-methyi propanoic acid compound of formula- 1 , herein after designated as crystalline form-M.
  • the crystalline form-M of compound of formula- 1 of the present invention is characterized by its PXRD pattern having peaks at 2.8, 5.7, 9. 1 ⁇ 0.2° of 2-theta and is further characterized by its PXRD pattern as illustrated in figure-2.
  • the another embodiment of the present invention provides a process for the preparation of crystalline form-M of 2-[4-(2- ⁇ 4-[l -(2-ethoxyethyi)-l H-benzimidazol-2-yl]- l - piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1 , comprising of; a) Dissolving the compound of formula- 1 in a mixture of dichloromethane and methanol, b) combining the solution with n-heptane at a suitable temperature,
  • step-a) the dissolution can be carried out at suitable temperature ranges from 20-35°C;
  • step-b) the suitable temperature ranges from -30°C to 30°C; preferably 0-5°C.
  • small amount of form-M seeding material can optionally be added to n-heptane before combining it with step-a) solution to facilitate the formation of crystalline form-M.
  • any physical form of compound of formula- 1 can be utilized as input for the preparation of crystalline form-M, crystalline form-2, pure amorphous form as well as amorphous solid dispersion of compound of formula- 1 .
  • the crystalline form-M, crystalline form-2, pure amorphous form as well as amorphous solid dispersion of compound of formula- 1 of the present invention can be further micronized to achieve desired particle size distribution in order to make suitable formulation.
  • the crystalline form-M crystalline form-2 and pure amorphous form of compound of formula- 1 of the present invention can be utilized as input for the preparation of any known polymorphic form of compound of formula- 1 and they can also be used in the preparation of other novel polymorphic forms of compound of formula- 1.
  • An embodiment of the present invention provides crystalline form-2 of compound of formula- 1 having particle size distribution of D90 less than 400 ⁇ , preferably less than 200 ⁇ , more preferably less than 100 ⁇ , most preferably less than 20 ⁇ .
  • the compound of formula- 1 of the present invention was analyzed by HPLC under the following conditions;
  • Apparatus A liquid chromatographic system equipped with variable wavelength UV detector; Column: Xbridge shield RP1 8 1 50 * 4.6 mm, 3.5 ⁇ or equivalent; Column temperature: 20°C; Wave length: 215 nm; Injection volume: 5 ⁇ ; Elution: Gradient; Diluent: Acetonitrile: Water (20:80 v/v); Buffer: Weigh accurately about 6.8 gm of potassium dihydrogen phosphate and add 2.5 gm of 1 -octane sulfonic acid sodium salt anhydrous into 1000 mL of milli-Q-water, mix well.
  • Example-1 Preparation of 2-f4-(2- ⁇ 4-
  • n-Butanol (500 ml) and sodium hydroxide (73.16 gm) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Heated the reaction mixture to 105- 1 10°C and stirred for 8 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with water. Water ( 1 000 ml) was added to the obtained compound, acidified the reaction mixture using acetic acid at 25-30°C and stirred for 40 min at the same temperature. Filtered the solid and washed with water. Dimethyl sulfoxide (300 ml) and n-butanol (300 ml) were added to the obtained compound at 25-30°C.
  • the PXRD pattern of the obtained compound is shown in figure- 1 .
  • Example-2 Preparation of crystalline form-2 of compound of formula-1
  • D(0. 1 ) is 1 .42 ⁇ ; D(0.5) is 13.73 ⁇ ; D(0.9) is 1 01 .81 ⁇ .
  • D(0. 1 ) is ⁇ ; D(0.5) is ⁇ ; D(0.9) is ⁇ .
  • D(0. 1 ) is 1 .00 ⁇ ; D(0.5) is 7.79 ⁇ ; D(0.9) is 56.49 ⁇ .
  • D(0.1 ) is 0.41 ⁇ ; D(0.5) is 2.05 ⁇ ; D(0.9) is 6.68 ⁇ .
  • Example-7 Alternate process for the preparation of pure amorphous form of compound of formula-1
  • Example-8 Preparation of amorphous solid dispersion comprising compound of formula-1 and Povidone K-30
  • a 1 1 mixture of methanol and dichloromethane (30 mi) was added to a mixture of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic' acid compound of formula- 1 (500 mg) and Povidone K-30 (500 mg) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Slowly heated the reaction mixture to 55-60°C and transferred the solution into a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and dried the material to provide the title compound.
  • Example-9 Preparation of amorphous solid dispersion comprising compound of formula-1 and hydroxypropyl cellulose (HPC)
  • a 1 1 mixture of methanol and dichloromethane (30 ml) was added to a mixture of 2- [4-(2- ⁇ 4-[ l -(2-ethoxyethyl)-l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1 (500 mg) and hydroxypropyl cellulose (500 mg) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Slowly heated the reaction mixture to 55-60°C and transferred the solution into a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to provide the title compound.
  • Example-10 Preparation of amorphous solid dispersion comprising compound of formula-1 and hydroxypropyl methyl cellulose (HPMC)
  • Example-11 Preparation of amorphous solid dispersion comprising compound of formula-1 and hydroxypropyl methyl cellulose acetate succinate (HP CAS)
  • a 1 1 mixture of methanol and dichloromethane (30 ml) was added to a mixture of 2-[4-(2- ⁇ 4-[ 1 -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 -piperidiny 1 ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula-1 (500 mg) and hydroxypropyl methyl cellulose acetate succinate (500 mg) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Slowly heated the reaction mixture to 55-60°C and transferred the solution into a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to provide the title compound.
  • Example-12 Preparation of amorphous solid dispersion comprising compound of formula-1 and Eudragit
  • a 1 1 mixture of methanol and dichloromethane (30 ml) was added to a mixture of 2-[4-(2- ⁇ 4-[ l -(2-ethoxyethyl)- l H-benzimidazol-2-yl]- l -piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1 (500 mg) and Eudragit (500 mg) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Slowly heated the reaction mixture to 55-60°C and transferred the solution into a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to provide the title compound.
  • Step-1
  • Dichloromethane (250 Lt) was added to the compound obtained in step- 1 at 25-30°C and stirred the reaction mixture for 10 min at the same temperature.
  • the obtained solution was slowly added to a pre-cooled mixture of sodium carbonate (39 Kg), water (250 Lt) and ⁇ , ⁇ - dimethylhydroxylamine hydrochloride (33.5 Kg) at 0-5°C under nitrogen atmosphere and stirred the reaction mixture for 30 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with dichloromethane. Both the organic and aqueous layers were separated from the filtrate and washed the organic layer with water. Distilled off the solvent completely from the organic layer. Dichloromethane ( 1 88 Lt) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 10 min at the same temperature and kept the reaction mixture aside.
  • Step -3
  • Aluminium trichloride (81 Kg) and dichloromethane (313 Lt) were charged into a reactor at 25-30°C under nitrogen atmosphere and cooled the reaction mixture to 0-5°C.
  • Chloroacetyl chloride (41 .5 Kg) was slowly added to the reaction mixture at 0-5°C and stirred the reaction mixture for 1 hr at the same temperature.
  • the reaction mixture obtained in step-2 was slowly added to the resulting reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hr at the same temperature.
  • the obtained reaction mixture was slowly added to pre-cooled water at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature.
  • the resulting reaction mixture was added to pre- cooled water at 0-5°C and raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium bicarbonate solution followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer.
  • the obtained compound was purified by si lica gel column chromatography using ethyl acetate/cyclohexane mixture as e!uent and collected the pure fractions. Disti lled off the solvent completely from the pure fractions under reduced pressure. Petroleum ether (25 Lt) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to -20°C to -25°C and stirred for 40 min at the same temperature. Filtered the solid, washed with chil led petroleum ether and dried the material to provide the title compound. Yield: 23.8 Kg.
  • n-Butanol (87.5 Lt) and sodium hydroxide ( 12.8 Kg) were added to the obtained compound at 25-30°C. Heated the reaction mixture to 105- 1 10°C and stirred for 7 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with water. Water ( 1 75 Lt) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C, acidified the reaction mixture using acetic acid and stirred for 20 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 40 min at the same temperature. Filtered the precipitated solid and washed with water.
  • the obtained solid was added to a mixture of dimethyl sulfoxide (35 Lt) and n-butanol (35 Lt) at 25-30°C. Heated the reaction mixture to 105- 1 10°C and stirred for 1 5 min at the same temperature. Reduced the temperature of the reaction mixture to 80-85°C and stirred for 2 hrs at the same temperature. Further cooled the reaction mixture to 25-30°C and stirred for 40 min at the same temperature. Filtered the precipitated solid and washed with n-butanol. The obtained solid was added to water (175 Lt) at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 40 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 40 min at the same temperature. Filtered the solid, washed with water and dried the material to provide the title compound.
  • dimethyl sulfoxide 35 Lt
  • n-butanol 35 Lt
  • n-Butanol (500 ml) and sodium hydroxide (73.1 6 gm) were added to the obtained compound at 25-30°C and stirred for 5 min at the same temperature. Heated the reaction mixture to 1 10- 1 1 5°C and stirred for 8 hrs at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure and co-disti lled with water. Water was added to the obtained compound at 25-30°C, acidified the reaction mixture by using acetic acid and stirred the reaction mixture for 40 min at the same temperature. Filtered the solid and washed with water. Dimethyl sulfoxide (300 ml) and n-butanol (300 ml) were added to the obtained compound at 25-30°C.
  • Dichloromethane (500 ml) was added to compound of formula- 1 (50 gm) at 25-30°C. Distilled off the solvent completely from the reaction mixture. Methanol ( 100 ml) and dichloromethane (350 ml) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 5 min at the same temperature. Fi ltered the reaction mixture and washed with dichloromethane. Distilled off the solvent completely from the filtrate. Dichloromethane (400 ml) and methanol (100 ml) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. The obtained solution was slowly added to pre-cooled methyl tert.
  • butyl ether (2500 ml) containing crystalline form-2 seeding material (5 gm) at -5°C to - 10°C and stirred the reaction mixture for 45 min at the same temperature. Filtered the solid and washed with methyl tert.butyl ether. The obtained material was added to pre-cooled cyclohexane (250 ml) at 10-15°C and stirred the reaction mixture for 45 min at the same temperature. Filtered the solid, washed with chilled cyclohexane and dried the material to get the title compound.
  • D(0.1 ) is 0.76 ⁇ ; D(0.5) is 5.41 ⁇ ; D(0.9) is 50.40 ⁇ .
  • the PX D pattern of the obtained compound is similar to figure-7 of WO2017017301 Al . Yield: 20.0 gm.

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Abstract

La présente invention concerne des formes à l'état solide d'acide 2-[4-(2-{4-[1 -(2-éthoxyéthyl)- 1H-benzimidazol-2-yl]-1-pipéridinyl}éthyl)phényl]-2-méthylpropanoïque représenté par la formule structurale 1 suivante et un procédé de préparation associé.
EP17792622.7A 2016-05-05 2017-05-02 Formes à l'état solide d'acide 2-[4-(2-{4-[1-(2-éthoxyéthyl)-1h-benzimidazol-2-yl]-1-pipéridinyl}éthyl)phényl]-2-méthylpropanoïque et procédé de préparation associé Withdrawn EP3452462A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641015655 2016-05-05
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