WO2014132270A2 - Procédé de préparation de monochlorydrate d'acétamide 2- (2-aminothiazol -4-yl)-n- [4- (2- {[ (2r) -2-hydroxy -2-phényl-éthyl] amino} éthyl) phényl], de ses intermédiaires et polymorphe de celui-ci - Google Patents

Procédé de préparation de monochlorydrate d'acétamide 2- (2-aminothiazol -4-yl)-n- [4- (2- {[ (2r) -2-hydroxy -2-phényl-éthyl] amino} éthyl) phényl], de ses intermédiaires et polymorphe de celui-ci Download PDF

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WO2014132270A2
WO2014132270A2 PCT/IN2014/000129 IN2014000129W WO2014132270A2 WO 2014132270 A2 WO2014132270 A2 WO 2014132270A2 IN 2014000129 W IN2014000129 W IN 2014000129W WO 2014132270 A2 WO2014132270 A2 WO 2014132270A2
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phenyl
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WO2014132270A3 (fr
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Suraparaju Raghuram
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MSN Laboratories Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention provides 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride salt compound of formula- la, its hydrates, polymorphs and rocess for preparation thereof.
  • the present invention also provides an improved process for the preparation of 2-(2- amino thiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide compound of formula- 1.
  • Background of the invention :
  • 2-(2-Aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl] acetamide commonly known as Mirabegron is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and urinary frequency. It was developed by Astellas Pharma and was approved in the United States on 28 th June 2012 and in Europe on 20 th Dec. 2012.
  • the said patent discloses a process for the preparation of dihydrochloride salt of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl]amino ⁇ ethyl)phenyl] acetamide, which comprising of deprotection of tert-butyl (R)- N-[2-[4-[2-(2-amino-thiazol-4-yl)acetamido]phenyl]ethyl]-N-[(2-hydroxy-2-phenyl)ethyl] carbamate (Boc protected Mirabegron) with hydrochloric acid in a mixture of methanol and ethyl acetate followed by purification of the obtained Mirabegron by reverse phase column chromatography using water/methanol (2: 1) as eluent.
  • Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound.
  • the difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum.
  • One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) as well as content of solvent in the polymorphic form, which have been used to distinguish polymorphic forms.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the first aspect of the present invention is to provide monohydrochloride salt of 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide.
  • the second aspect of the present invention is to provide crystalline form of 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride compound of formula- la, herein after referred as crystalline form-M.
  • the third aspect of the present invention is to provide a process for the preparation of 2- (2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride salt compound of formula- la.
  • the fourth aspect of the present invention is to provide a process for the preparation of N-benzyl-2-(4-nitrophenyl)ethanamine compound of formula-8, comprising of reductive amination of benzaldehyde with 2-(4-nitrophenyl)ethanamine compound of formula-3 to provide N-benzyl-2-(4-nitrophenyl)ethanamine compound of formula-8.
  • the fifth aspect of the present invention is to provide another process for the preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl )phenyl] acetamide monohydrochloride salt compound of formula- 1 a.
  • the sixth aspect of the present invention is to provide a process for the preparation of (2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide compound of formula- 1.
  • Figure-1 Illustrates the PXRD pattern of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl] amino ⁇ ethyl)phenyl]acetamide monohydrochloride (Formula- 1 a).
  • Figure-2 Illustrates the DSC thermogram of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2- hydroxy-2-phenylethyl] amino ⁇ ethyl)phenyl] acetamide monohydrochloride (Formula- 1 a) .
  • FIG. 3 Illustrates the thermogravimetric analysis (TGA) curve of 2-(2-aminothiazol-4-yl)-N- [4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride (Formula- la).
  • TGA thermogravimetric analysis
  • Figure-4 Illustrates the PXRD pattern of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride (Formula- la) obtained according to example- 15.
  • Figure-5 Illustrates the PXRD pattern of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl]amino ⁇ ethyl)phenyl]acetamide (Formula-1).
  • suitable solvent refers to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane, pet ether, chlorobenzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, di- tert-butyl ether, dimethoxy methane, 1,2-dimethoxy ethane (monoglyme), diglyme, 1,4- dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, morpholine and the like; "ester solvents” such as methyl acetate, ethyl acetate,
  • suitable base refers to "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA) and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and “organic bases”
  • the first aspect of the present invention provides monohydrochloride salt of 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide.
  • the said monohydrochloride salt of the present invention can exists in the form of
  • the second aspect of the present invention provides crystalline form of 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride salt compound of formula- la characterized by its powder X-ray diffraction pattern having peaks at 2.1, 4.3, 6.4, 8.5, 17.4, 19.3, 21.6, 24.3, 24.8, 27.3, 31.6, 45.4 ⁇ 0.2 degrees of 2-theta.
  • the said crystalline form is herein after designated as crystalline form-M.
  • the said crystalline form-M is further characterized by its PXRD pattern as illustrated in figure- 1 and its differential scanning calorimetric (DSC) thermogram having an endotherm at 201.03°C substantially in accordance with figure-2.
  • the third aspect of the present invention provides a process for the preparation of 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride salt compound of formula- 1 a, comprising of;
  • step-(e) treating the dihydrochloride salt obtained in step-(e) in-situ with a suitable aqueous base to provide 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl) phenyl] acetamide monohydrochloride salt compound of formula- la.
  • the suitable coupling agent is selected form N,N-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides such as ⁇ , ⁇ -diisopropylcarbodiimide (DIC), N,N- dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), ditolyl carbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo- NHS); carbonyl-di-l,2,4-triazole; alkyl and aryl halo formates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate; carbonates having the formula R1-O-CO-O-R2, where
  • the suitable reducing agent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH 4 , NaBH 4 /BF 3 .diethyl ether, LiBH 4 , LiAlH 4 and the like; and the suitable solvent is selected from alcoholic solvent, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, polar aprotic solvents or mixtures thereof;
  • step-c) the conversion of compound of formula-5 into its HCl salt compound of formula-5a is carried out by using a suitable HCl source selected from HCl gas, HCl, aq.HCl, ethylacetate-HCl and IPA-HC1 in a suitable solvent.
  • a suitable HCl source selected from HCl gas, HCl, aq.HCl, ethylacetate-HCl and IPA-HC1 in a suitable solvent.
  • the suitable reducing agent is selected from Fe, Fe in acidic media like NH 4 C1 or HCl or acetic acid, Sn in acidic media like HCl, Zn dust, Zn in acidic media like HCl or NH 4 CI or acetic acid, stannous chloride (SnCl 2 ), NaB3 ⁇ 4, LiAlH 4i LiBH 4 , diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Pd/C, Pt/C, Pt0 2 , Pd(OH) 2 , Nickel, Raney nickel, Rhodium, sodium dithionate, sodium amalgam and the like; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, polar solvents, hydrocarbon solvents or mixtures thereof;
  • step-e) the suitable coupling agent & suitable solvent are same as defined in step-(a); in step-f) the suitable base can be selected from hydroxides, carbonates and bicarbonates of alkali metals.
  • a preferred embodiment of the present invention provides a process for the preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-henylethyl]amino ⁇ ethyl)phenyl]acetamide mono hydrochloride salt compound of formula- la, comprising of;
  • step-(e) treating the dihydrochloride salt obtained in step-(e) in-situ with aqueous sodium hydroxide solution to provide 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl] amino ⁇ ethyl)phenyl]acetamide monohydrochloride compound of formula- la.
  • US7342117B2 patent discloses the reduction of (R)-2-hydroxy-N-(4-nitrophenethyl)-2- phenylacetamide compound of formula-4 to (R)-2-(4-nitrophenethylamino)-l-phenylethanol compound of formula-5 using borane-THF complex in a mixture of l,3-dimethyl-2- imidazolidinone (DMI) and tetrahydrofuran.
  • DMI 1, 3 -dimethyl-2 -imidazolidinone
  • DI 1, 3 -dimethyl-2 -imidazolidinone
  • the present inventors carried out the said reduction step in tetrahydrofuran, thereby avoiding the usage of toxic and high boiling solvents like l,3-dimethyl-2-imidazolidinone (DMI), hence the process of the present invention is advantageous over prior-art process.
  • DMI toxic and high boiling solvents like l,3-dimethyl-2-imidazolidinone
  • the 2-(4-nitrophenyl)ethanamine compound of formula-3 utilized in step-(a) of the third aspect of the present invention can be synthesized by any of the prior reported processes, for example it can be synthesized by the processes disclosed in J. Org. Chem., 1978, 43(1), 31-33 and Tetrahedron Letters, Volume 10, Issue 52, 1969, 4555-4558.
  • the 2-(2-aminothiazol-4-yl)acetic acid compound of formula-7 utilized in step-(e) of the third aspect of the present invention can be synthesized by any of the processes known in the art such as US4391979A.
  • the fourth aspect of the present invention provides a process for the preparation of N- benzyl-2-(4-nitrophenyl)ethanamine compound of formula-8,
  • the reductive amination step is carried out in presence of a suitable reducing agent selected form NaBH 4 , sodium cyanoborohydride, sodium triacetoxyborohydride, trihalosilanes, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride, lithium tri- sec-butyl borohydride (L-selectride), trialkylsilanes optionally in combination with trifluoroacetic acid, hydrogenating agents like Pd/C, Pt/C, Ni, Raney Ni and the like in a suitable solvent selected from alcoholic solvents, ether solvents, ester solvents, polar solvents, hydrocarbon solvents, polar-aprotic solvents or mixtures thereof.
  • a suitable reducing agent selected form NaBH 4 , sodium cyanoborohydride, sodium triacetoxyborohydride, trihalosilanes, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride,
  • a preferred embodiment of the present invention provides a process for the preparation of N-benzyl-2-(4-nitrophenyl)ethanamine compound of formula-8, comprising of reductive amination of benzaldehyde with 2-(4-nitrophenyl)ethanamine compound of formula-3 in presence of sodium borohydride in methanol to provide N-benzyl-2-(4-nitrophenyl)ethanamine compound of formula-8.
  • the fifth aspect of the present invention provides a process for the preparation of 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide monohydrochloride salt compound of formula- la, comprising of;
  • suitable reducing agent and the suitable solvent are same as defined in fourth aspect of the present invention; in step-b) the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, polar solvents, hydrocarbon solvents, ketone solvent, polar-aprotic solvents or mixtures thereof;
  • the suitable reducing agent is selected from Pd/C, Pt/C, Raney Ni, Pt0 2 and the like; and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, polar solvents, hydrocarbon solvents or mixtures thereof;
  • step-d) the suitable coupling agent and suitable solvent are same as defined in step-(a) of the third aspect of the present invention.
  • step-e) the suitable base is same as defined for step-(f) of the third aspect of the present invention.
  • the sixth aspect of the present invention provides a process for the preparation of 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl]acetamide compound of formula- 1, comprising of:
  • step-a) the suitable coupling agent, the suitable base and suitable solvent are same as defined in step-(a) of third aspect of the present invention.
  • step-b) the suitable reducing agent and suitable solvent are same as defined in step-(b) of third aspect of the present invention respectively;
  • step-c) the suitable reducing agent and suitable solvent is same as defined in step-(d) of third aspect of the present invention.
  • step-d) the suitable coupling agent and suitable solvents are same as defined in step-(a) of third aspect of the present invention.
  • the suitable solvent is alcoholic solvents; the anti-solvent is selected from polar solvents.
  • a preferred embodiment of the present invention provides a process for the preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl]amino ⁇ ethyl)phenyl]acetamide compound of formula- 1, comprising of:
  • step-(d) purifying the compound obtained in step-(d) by dissolving the compound in methanol followed by adding water to provide pure compound of formula- 1.
  • 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl] acetamide obtained by the present invention is having purity about 99.8% by HPLC. All the impurities that are formed during the synthesis of compound of formula- 1 and its mono hydrochloride salt of formula- la are controlled to below ICH limits in which few of them are controlled to not detected level.
  • a liquid chromatograph is equipped with variable wavelength UV-detector; Column: symmetry shield RP18, 250 x 4.6 mm, 5 ⁇ or equivalent; Flow rate: 1.0 ml/minute; Elution: Gradient; Wavelength: 210 nm; Column temperature: 45°C; Injection volume: 5 ⁇ ; Run time: 45 mins; Needle wash: Diluent; Diluent: water: acetonitrile (50:50 v/v); Mobile phase A: Buffer : Methanol (70: 30 v/v); Mobile phase B: Acetonitrile : Buffer (70:30 v/v); Buffer preparation: Transfer about 1.74 gms of anhydrous Di potassium hydrogen phosphate and 3 gms of anhydrous 1 -octane sulfonic acid sodium salt in 1000 ml of milli-Q-water, adjust its pH of to 5.0 with dil.ortho phosphoric acid and filter this solution through 0.22 ⁇
  • DSC Differential scanning calorimetric
  • TGA Thermogravimetric analysis
  • 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl] acetamide and its monohydrochloride salt produced by the present invention can be further micronized or milled to get the desired particle size, preferably less than 20 ⁇ to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.
  • Milling or micronization may be performed before drying or after the completion of drying of the product. The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
  • Example-1 Preparation of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (or) (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (Formula-4)
  • Example-2 Preparation of (R)-2-[[2'-(4-nitrophenyl)-ethyl]amino]-l-phenyIethanol mono hydrochloride (or) (R)-2-(4-nitrophenethylamino)-l-phenylethanol mono hydrochloride (Formula-5a)
  • Example-3 Preparation of (R)-2-[ ⁇ 2-(4-aminophenyl)ethyI]-amino]-l-phenyIethanoI monohydrochloride (or) (R)-2-(4-aminophenethylamino)-l-phenylethanol mono hydrocloride
  • Iron powder (86.8 gms) was added to a mixture of (R)-2-[[2'-(4-nitrophenyl)- ethyl] amino] -1 -phenylethanol monohydrochloride compound of formula-5a (100 gms), tetrahydrofuran (500 ml) and water (500 ml) at 25-30°C and stirred for 15 min at the same temperature.
  • tetrahydrofuran 500 ml
  • water 500 ml
  • hydrochloric acid 124 ml
  • Example-5 Preparation of 2-(2-aminothiazoI-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl] amino ⁇ ethyl)phenyl]acetamide monohydrochloride (Formula-la) 2-aminothiazol-4-yl-acetic acid (or) 2-(2-aminothiazol-4-yl)acetic acid compound of formula-7 (2.76 gms) was added to a mixture of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l- phenylethanol monohydrochloride compound of formula-6a (5.0 gms), hydrochloric acid (4.62 ml) and water (30 ml) at 25-30°C and stirred for 15 mins at the same temperature.
  • EDC.HC1 l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • Example-6 Preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl]amino ⁇ ethyI)phenyl]acetamide monohydrochloride (Formula-la)
  • 2-aminothiazol-4-yl-acetic acid compound of formula-7 (5.5 gms) was added to a mixture of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol compound of formula-6 (10 gms), hydrochloric acid (3.5 gms) and water (75 ml) at 25-30°C.
  • a solution of l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1) (7.5 gms of EDC.HC1 dissolved in 120 ml of water) was added slowly to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature.
  • Aqueous sodium hydroxide solution (3.13 gms of sodium hydroxide dissolved in 30 ml of water) was added to the reaction mixture and stirred for 90 mins at 25- 30°C. Filtered the precipitated solid, washed with water and dried to get title compound.
  • Example-10 Preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl] amino ⁇ ethyl)phenyl]acetamide monohydrochloride (Formula-la) 2-aminothiazol-4-yl-acetic acid compound of formula-7 (2.76 gms) was added to a mixture of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol compound of formula-6 (5.0 gms), hydrochloric acid (4.62 ml) and water (30 ml) at 25-30°C and stirred the reaction mixture for 15 mins at the same temperature.
  • the TGA of the obtained compound is shown in figure-3, which indicates that the obtained 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl] acetamide monohydrochloride salt is anhydrous in nature.
  • EDC.HCl l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • EDC.HCl hydroxybenztriazole
  • HOBt hydroxybenztriazole
  • R -2-hydroxy-2-phenylacetic acid compound of formula-2
  • triethylamine 49.8 gms
  • 2-(4- nitrophenyl)ethylamine hydrochloride compound of formula-3a 100 gms
  • N-methyl-2- pyrrolidone 400 ml
  • Example-13 Preparation of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanoI (Formula-6)
  • l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (222.3 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 0-5°C. pH of the reaction mixture was adjusted to 9.0 using aqueous sodium hydroxide solution (66.9 gms of sodium hydroxide dissolved in 1350 ml of water) at 0-5°C and stirred for 90 mins at 0-5°C. Filtered the precipitated solid and washed with water. Water (1200 ml) was added to the obtained solid at 25-30°C and stirred for 90 mins at the same temperature.
  • Chloride content 8.12% w/w; Water content: 0.27% w/w.
  • Example-16 Preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl] amino ⁇ ethyl)phenylJacetamide (Formula-1)
  • 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2-phenylethyl]amino ⁇ ethyl)phenyl] acetamide can be prepared according to example- 14 by using 2-aminothiazol-4-yl-acetic acid hydrochloride compound of formula- 7a in place of 2-aminothiazol-4-yl-acetic acid compound of formula-7.
  • Example-17 Preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2- phenylethyl] amino ⁇ ethyl)phenyl]acetamide (Formula- 1)

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Abstract

La présente invention concerne un procédé de préparation du composé monochlorhydrate d'acétamide 2- (2-aminothiazol -4-yl)-N- [4- (2- {[ (2R) -2-hydroxy -2-phényléthyl] amino} éthyl)phényl] de formule-la, de ses intermédiaires et polymorphe de celui-ci. [insérer la Formule ici]
PCT/IN2014/000129 2013-02-27 2014-02-26 Procédé de préparation de monochlorydrate d'acétamide 2- (2-aminothiazol -4-yl)-n- [4- (2- {[ (2r) -2-hydroxy -2-phényl-éthyl] amino} éthyl) phényl], de ses intermédiaires et polymorphe de celui-ci Ceased WO2014132270A2 (fr)

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WO2015040605A1 (fr) * 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Forme cristalline de mirabegron
CN105111165A (zh) * 2015-09-14 2015-12-02 河南师范大学 一种米拉贝隆的制备方法
WO2016049749A1 (fr) * 2014-10-01 2016-04-07 Apotex Inc. Formes solides du mirabégron
CN106278909A (zh) * 2016-08-12 2017-01-04 浙江华海药业股份有限公司 一种米拉贝隆中间体的后处理方法
WO2017137784A1 (fr) * 2016-02-10 2017-08-17 Egis Gyógyszergyár Zrt. Procédé de production de mirabegron morphologiquement homogène et de monochlorhydrate de mirabegron
WO2017149332A1 (fr) * 2016-02-01 2017-09-08 Egis Gyógyszergyár Zrt. Co-cristal de mirabegron
CN109456277A (zh) * 2018-10-29 2019-03-12 安徽省庆云医药股份有限公司 一种米拉贝隆的制备方法
CN109651290A (zh) * 2018-10-31 2019-04-19 安徽省庆云医药股份有限公司 一种米拉贝隆的制备方法
WO2019081972A1 (fr) 2017-08-09 2019-05-02 Saneca Pharmaceuticals A.S. Procédé de préparation d'acide mandélique 4-nitrophényl éthylamide à partir de cyanure de 4-nitrobenzyle
CN111205151A (zh) * 2020-02-29 2020-05-29 深圳市祥根生物科技有限公司 一种布洛芬杂质i的环保制备方法
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KR20210073972A (ko) * 2019-12-11 2021-06-21 주식회사 다산제약 (r)-2-((4-아미노페네틸)아미노)-1-페닐에탄올의 신규한 제조방법
CN113816864A (zh) * 2020-06-18 2021-12-21 南京正大天晴制药有限公司 一种(r)-2-羟基-n-[2-(4-氨基苯基)乙基]-2-苯乙胺的制备方法
CN121270488A (zh) * 2025-12-09 2026-01-06 浙江工业大学 一种微通道反应器连续制备米拉贝隆的方法

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WO2015040605A1 (fr) * 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Forme cristalline de mirabegron
CN104230840A (zh) * 2014-09-05 2014-12-24 安徽联创药物化学有限公司 米拉贝隆的合成方法
WO2016049749A1 (fr) * 2014-10-01 2016-04-07 Apotex Inc. Formes solides du mirabégron
CN105111165A (zh) * 2015-09-14 2015-12-02 河南师范大学 一种米拉贝隆的制备方法
WO2017149332A1 (fr) * 2016-02-01 2017-09-08 Egis Gyógyszergyár Zrt. Co-cristal de mirabegron
WO2017137784A1 (fr) * 2016-02-10 2017-08-17 Egis Gyógyszergyár Zrt. Procédé de production de mirabegron morphologiquement homogène et de monochlorhydrate de mirabegron
CN106278909A (zh) * 2016-08-12 2017-01-04 浙江华海药业股份有限公司 一种米拉贝隆中间体的后处理方法
WO2018028679A1 (fr) * 2016-08-12 2018-02-15 浙江华海药业股份有限公司 Procédé de post-traitement pour un intermédiaire de mirabegron
CN106278909B (zh) * 2016-08-12 2022-07-15 浙江华海药业股份有限公司 一种米拉贝隆中间体的后处理方法
WO2019081972A1 (fr) 2017-08-09 2019-05-02 Saneca Pharmaceuticals A.S. Procédé de préparation d'acide mandélique 4-nitrophényl éthylamide à partir de cyanure de 4-nitrobenzyle
CN109456277B (zh) * 2018-10-29 2022-04-22 安徽省庆云医药股份有限公司 一种米拉贝隆的制备方法
CN109456277A (zh) * 2018-10-29 2019-03-12 安徽省庆云医药股份有限公司 一种米拉贝隆的制备方法
CN109651290A (zh) * 2018-10-31 2019-04-19 安徽省庆云医药股份有限公司 一种米拉贝隆的制备方法
CN109651290B (zh) * 2018-10-31 2022-04-01 安徽省庆云医药股份有限公司 一种米拉贝隆的制备方法
KR20210073972A (ko) * 2019-12-11 2021-06-21 주식회사 다산제약 (r)-2-((4-아미노페네틸)아미노)-1-페닐에탄올의 신규한 제조방법
KR102350458B1 (ko) 2019-12-11 2022-01-12 주식회사 다산제약 (r)-2-((4-아미노페네틸)아미노)-1-페닐에탄올의 신규한 제조방법
CN111205151A (zh) * 2020-02-29 2020-05-29 深圳市祥根生物科技有限公司 一种布洛芬杂质i的环保制备方法
CN111440126A (zh) * 2020-04-03 2020-07-24 湖南复瑞生物医药技术有限责任公司 一种米拉贝隆的制备方法
CN111440126B (zh) * 2020-04-03 2023-11-28 湖南复瑞生物医药技术有限责任公司 一种米拉贝隆的制备方法
CN113816864A (zh) * 2020-06-18 2021-12-21 南京正大天晴制药有限公司 一种(r)-2-羟基-n-[2-(4-氨基苯基)乙基]-2-苯乙胺的制备方法
CN113816864B (zh) * 2020-06-18 2024-03-29 南京正大天晴制药有限公司 一种(r)-2-羟基-n-[2-(4-氨基苯基)乙基]-2-苯乙胺的制备方法
CN121270488A (zh) * 2025-12-09 2026-01-06 浙江工业大学 一种微通道反应器连续制备米拉贝隆的方法

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