WO2015044965A4 - A process for preparation of mirabegron and alpha crystalline form thereof - Google Patents
A process for preparation of mirabegron and alpha crystalline form thereof Download PDFInfo
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- WO2015044965A4 WO2015044965A4 PCT/IN2014/000637 IN2014000637W WO2015044965A4 WO 2015044965 A4 WO2015044965 A4 WO 2015044965A4 IN 2014000637 W IN2014000637 W IN 2014000637W WO 2015044965 A4 WO2015044965 A4 WO 2015044965A4
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- TUAHDMSPHZSMQN-INIZCTEOSA-N Nc1ccc(CCNC[C@@H](c2ccccc2)O)cc1 Chemical compound Nc1ccc(CCNC[C@@H](c2ccccc2)O)cc1 TUAHDMSPHZSMQN-INIZCTEOSA-N 0.000 description 2
- 0 C*(C)CC(Cc(cc1)ccc1N)NC[C@](c1ccccc1)O Chemical compound C*(C)CC(Cc(cc1)ccc1N)NC[C@](c1ccccc1)O 0.000 description 1
- JDKAPHATKPUAPT-FQEVSTJZSA-N C=NN(C(Cc1c[s]c(N)n1)=O)c1ccc(CCNC[C@@H](c2ccccc2)O)cc1 Chemical compound C=NN(C(Cc1c[s]c(N)n1)=O)c1ccc(CCNC[C@@H](c2ccccc2)O)cc1 JDKAPHATKPUAPT-FQEVSTJZSA-N 0.000 description 1
- DYCLHZPOADTVKK-UHFFFAOYSA-N Nc1nc(CC(O)=O)c[s]1 Chemical compound Nc1nc(CC(O)=O)c[s]1 DYCLHZPOADTVKK-UHFFFAOYSA-N 0.000 description 1
- GXTZAIGFWQRDSQ-INIZCTEOSA-N [O-][N+](c1ccc(CCNC[C@@H](c2ccccc2)O)cc1)=O Chemical compound [O-][N+](c1ccc(CCNC[C@@H](c2ccccc2)O)cc1)=O GXTZAIGFWQRDSQ-INIZCTEOSA-N 0.000 description 1
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- 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
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An improved process for the preparation of Mirabegron of formula (I) where 4- nitrophenylethylamine of formula (III) or its acid addition salt of formula (IlIa) reacted with compound of formula (XII) in a solvent, optionally in presence of base and/or catalyst to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of formula (XIII) followed by reducing (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of formula (XIII) in a solvent to obtain (R)-2-[2'-(4-nitrophenyl)ethyl]amino]-l-phenylethanol of formula (XIV), optionally converting it into its acid addition salt of formula (XlVa); reducing (R)-2-[2'-(4- nitrophenyl)ethyl]amino]-l -phenylethanol of formula (XIV) or its acid addition salt of formula (XlVa) further in solvent to obtain (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l -phenylethanol of formula (XV) or its acid addition salt of formula (XVa) respectively; and reacting compound (R)- 2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol of formula (XV) or its acid addition salt of compound of formula (XVa) with compound of formula (VII) in solvent, optionally in the presence of acid, and/or a catalyst to obtain Mirabegron of formula (I) which is further isolated as its a- crystalline form. The compound of formula (XIV) used in the foregoing process can also be prepared by reacting with a compound of formula (III) or acid addition salt of compound of formula (IlIa) in presence of a solvent, a catalyst and optionally in presence of a base to obtain compound of formula (XIV) optionally converting it into its acid addition salt of formula (XlVa); and the same is used in the above-referred process. The compound of formula (XV) used in the foregoing process can also be prepared by reacting a compound of formula (III) or its acid addition salt of formula (IlIa) with a compound of formula (XVI) in a solvent, optionally in presence of a base, optionally in presence of a catalyst to obtain compound of formula (XVII); and optionally isolate the compound of formula (XVII) followed by reducing the compound of formula (XVII) using reducing agent, in a solvent, optionally in presence of a base, optionally in presence of a catalyst to obtain compound of formula (XV) which is further used in the above- referred process for the preparation of Mirabegron of formula (I) and its a-crystalline form. Another additional single-pot process for preparation of Mirabegron of formula (I) is disclosed, wherein compound of formula (XV) or its acid addition salt of formula (XVa) reacted with compound of formula (XVIII) in presence of a solvent and oxidizing agent, optionally in presence of base, optionally in presence of a catalyst to obtain Mirabegron of formula (I).
Claims
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AMENDED CLAIMS
received by the International Bureau on 01 May 2015 (01.05.2015)
We claim,
An improved process for the preparation of a-crystalline form of Mirabegron of formula (I),
said process comprising;
reacting 4-nitrophenylethylamine of formula (III) or its acid addition salt of formula (Ilia) with compound of formula (XII) in presence of a solvent and reagent, optionally in presence of base, and/or catalyst to obtain (i?)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2- phenylacetamide of formula (XIII);
b) reducing (i?)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of formula (XIII) in presence of reducing agent and a solvent to obtain (i?)-2-[2'-(4- nitrophenyl)ethyl]amino]-l-phenylethanol of formula (XIV), optionally converting it into its acid addition salt of formula (XIV a);
c) reducing (i?j-2-[2'-(4-nitrophenyl)ethyl]amino]-l-phenylethanol of formula (XIV) or its acid addition salt of formula (XIV a) in solvent to obtain (i?)-2-[[2-(4-aminophenyl)ethyl]- amino]-l-phenylethanol of formula (XV) or its acid addition salt of formula (XVa) respectively;
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d) reacting compound (i?)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol of formula (XV) or its acid addition salt of formula (XVa) obtained in the step (c) with compound of formula (VII) in the presence of solvent, acid and a condensing agent, optionally in the presence of a catalyst to obtain Mirabegron of formula (I);
e) Isolating a-crystalline form of Mirabegron of formula (I) obtained in step (d) by
ia. adding first solvent to the reaction mass of step (d),
iia. basifying the solution of step (ia) and optionally heating the reaction mixture, iiia. separating the organic layer,
iva. extracting the aqueous layer with solvent, and combining the obtained organic layer with organic layer of step (iiia),
va. washing the combined organic layer with aqueous base followed by water, separating the organic layer and optionally distilling the organic layer; and
via. adding second solvent to organic layer of step (va) to obtain α-crystalline form of Mirabegron of compound of Formula (I); and
optionally purifying by solvent crystallization.
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2. The process as claimed in claim 1 , wherein the reagent used in steps (a) are selected from borane reagents such as boric acid, phenyl boronic acid and trimethyl borate; carbodiimide reagents such as N, N'-dicyclohexylcarbodiimide (DCC) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC) or its salt; or imidazole reagents such as 1,1'- carbonyldiimidazole (CDI).
3. The process as claimed in claim 1, wherein the solvent used in step (a) is selected from alcohols such as methanol, ethanol, isopropanol and n-butanol; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbon such as dichloromethane and dichloroethane; formamide such as N,N-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethylsulfoxide; cyclic amides such as N-Methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate and isopropyl acetate; or a mixture thereof.
4. The process as claimed in claim 1, wherein the base used in step (a) may be organic or inorganic base; organic bases selected from l,8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as methylamine, propyl amine, 2- propyl amine, and butyl amine; secondary amines such as Ν,Ν-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine and morpholine; tertiary amines such as triethylamine, Ν,Ν-dimethyl aniline, Ν,Ν-diisopropyl ethyl amine and trimethyl amine; inorganic bases selected from alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert butoxide;
5. The process as claimed in claim 1, wherein the step (a) further comprises isolation of compound of formula (XIII);
the said process comprises the steps of :
i. treating the reaction mass of step (a) with water;
ii. extracting the aqueous layer of step (i) with first solvent;
iii. separating the organic layer of step (ii) followed by washing it with acid, base and brine;
iv. concentrating the organic layer of step (iii); and
v. adding second solvent to the step (iv) to obtain compound of formula (XIII).
6. The process as claimed in claim 5, wherein the first solvent used in step (ii) is selected from the group comprising of aromatic hydrocarbons such as toluene and xylene,; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane; carboxylic acid esters such as ethyl acetate, methyl acetate and isopropyl acetate; ethers such as diethyl ether, diisopropyl ether, di-methyl ether and methyl tertiary butyl ether; substituted cyclic ether such as 2-methyltetrahydrofuran; or mixtures thereof.
7. The process as claimed in claim 5, wherein the second solvent used in step (v) is selected from the group comprising of aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, methyl acetate and isopropyl acetate; nitriles such as acetonitrile; ethers such as diisopropyl ether and methyl tertiary butyl ether; cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol and isopropyl alcohol; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; or mixtures thereof.
8. The process as claimed in claim 1, wherein the reducing agent used in step (b) is selected from lithium aluminium hydride, sodium borohydride in presence of Iodine; or sodium borohydride in presence of acids, wherein acids are selected from sulfuric acid, acetic acid, trifluoroacetic acid, zinc chloride (ZnCl2), cobalt chloride (CoCl2); sodium borohydride and BF3etherate; sodium borohydride and R2SeX2, where R is any alkyl and X is halide group; and diborane solutions such as BH3:THF, BH3:SMe2 and BH3:NR3.
9. The process as claimed in claim 1, wherein the solvent used in step (b) is selected from C2 to C8 straight chain, branched chain or cyclic ethers such as tetrahydrofuran and 2- methyltetrahydrofuran; hydrocarbons such as toluene, xylene, heptane, pentane and cyclohexane; nitriles such as acetonitrile; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; hexamethylphosphoroustriamide (HMPT); hexamethylphosphoramide (HMPA); or mixture thereof.
10. The process as claimed in claim 1, wherein the step (b) further comprises isolation of the compound of formula (XIV) or its acid addition salt of compound of formula (XIV a); said process comprises the steps of:
A. quenching the reaction mass of step (b) with alcoholic solvent and aqueous acid solution followed by addition of water;
B. concentrating the reaction mass, adding organic solvent followed by basifying the reaction mass;
C. separating the organic layer and washing the organic layer with aqueous solution of base;
D. acidifying the organic layer of step (C) to provide acid addition salt of compound of formula (XlVa) as a solid; and
E. filtering the solid and washing it with organic solvent followed by drying it to obtain pure compound of formula (XIV a) and optionally purifying the compound of (XIV a).
11. The process as claimed in claim 10, wherein optionally, concentrating the organic layer of step (C) and adding anti solvent to the concentrated organic layer to obtain free base compound of formula (XIV) and optionally purifying the compound of (XIV).
12. The process as claimed in claim 10, wherein the organic solvent used in step (B) is selected from the group comprising of aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptanes; halogenated hydrocarbons such as dichloromethane and dichloroethane; carboxylic acid esters such as ethyl acetate, methyl
acetate and isopropyl acetate; ethers such as diisopropyl ether and methyl tertiary butyl ether; substituted cyclic ether such as 2-methyltetrahydrofuran; or mixtures thereof.
13. The process as claimed in claim 10, wherein the base used in step (B and C) for basification is selected from inorganic bases such as ammonium hydroxide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, calcium bicarbonate and ammonium bicarbonate; and organic bases selected from triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine and pyridine and their mixtures thereof.
14. The process as claimed in claim 10, wherein the acid used in step (D) for acidification is selected from organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, oxalic acid, isopropyl alcohol hydrochloride solution and ethyl acetate hydrochloride solution.
15. The process as claimed in claim 10, wherein the organic solvent used in step (E) is selected from the group comprising of aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane and dichloroe thane; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, methyl acetate and isopropyl acetate; nitriles such as acetonitrile; ethers such as diisopropyl ether and methyl tertiary butyl ether; cyclic ethers such as tetrahydrofuran and 2-methyl tetrahydrofuran; or mixture thereof;
16. The process as claimed in claim 10, wherein the purification of compound of formula (XIV) or (XIV a) comprise solvent mediated crystallization; the crystallization process involve providing the solution of compound of formula (XIV) or (XIV a) in an alcoholic solvent and adding an anti-solvents to provide the pure compound of formula (XIV) or (XlVa).
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17. The process as claimed in claim 16, wherein the alcoholic solvent used for purification of compound of formula (XIV) or (XlVa) is selected from methanol, ethanol and isopropanol.
18. The process as claimed in claim 16, wherein the anti-solvent used in purification of compound of formula (XIV) or (XlVa) is selected from aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbon such as dichloromethane and dichloroe thane; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate and isopropyl acetate; or a mixture thereof.
19. The process as claimed in claim 1, wherein the reduction step (c) can be carried out either by catalytic reduction in presence of catalyst selected from palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon and raney nickel and in presence of hydrogen gas or hydrogen generating source such as ammonium formate and hydrazine hydrate; or metallic reduction in presence of metals such as iron, zinc and tin and in presence of acid selected from formic acid, acetic acid and hydrochloric acid and/or solvent; or chemical reduction in presence of sodium dithionate.
20. The process as claimed in claims 1 and 19, wherein the solvent used in the step (c) is selected from C3 to C6 amides such as dimethylformamide and dimethylacetamide; N- methylpyrrolidone; Ci to C6 straight or branched chain alcohols such as methanol, ethanol and isopropanol; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; C2 to C$ straight chain or cyclic ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, diisopropyl ether and methyl-tert-butyl; esters such as ethyl acetate, methyl acetate and isopropyl acetate; or a mixture thereof.
The process as claimed in claim 1, wherein the step (c) further comprises isolation of the compound of formula (XV) or its acid salts of compound of formula (XVa);
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the said process comprises the steps of;
I. recovering the catalyst by filtering the reaction mass of step (c) and concentrating the organic layer;
II. adding solvent to the concentrated layer to obtain the solid; and
III. filtering and washing the solid to obtain compound of formula (XV) or (XV a).
22. The process as claimed in claim 21, wherein the solvent used in step (II) is selected from alcohols such as methanol, ethanol, isopropanol and n-butanol; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbon such as dichlorome thane and dichloroe thane; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate and isopropyl acetate; or a mixture thereof.
23. The process as claimed in claim 21, wherein optionally, compound of formula (XV) or (XV a) obtained in step (III) can be purified with a solvent or solvent mixture; optionally by heating it at a temperature between room temperature to reflux temperature of the solvent.
24. The process as claimed in claim 23, wherein the solvent or solvent mixtures used for the purification of compound of formula (XV) or (XVa) is selected from alcohols such as methanol, ethanol, isopropanol and n-butanol; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbon such as dichloromethane and dichloroethane; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate and isopropyl acetate; or a mixture thereof.
25. The process as claimed in claim 1, wherein the solvent used in step (d) is selected from water, alcohols such as methanol, ethanol, isopropanol and n-butanol; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and
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heptane; halogenated hydrocarbon such as dichloromethane and dichloroethane; formamide such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethylsulfoxide; cyclic amides such as N-Methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate and isopropyl acetate; ionic liquids; or a mixture thereof.
26. The process as claimed in claim 1, wherein the acid used in step (d) is selected from hydrochloric acid, hydrobromic acid and sulfuric acid.
27. The process as claimed in claim 1, wherein the condensing agent used in the step (d) is selected from Ν,Ν'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) or its acid addition salts and 1, 1'- carbonyldiimidazole (CDI); optionally borane reagents selected from phenyl boronic acid, boric acid and trimethyl borate.
28. The process as claimed in claim 1, wherein alternatively, the organic layer obtained in step (va) is cooled, filtered and dried to obtain a-crystalline form of Mirabegron of formula (I).
29. The process as claimed in claim 1, wherein the first solvent used in step (ia) for extraction and solvent used in step (iva) for extraction is selected from the group comprising of aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate, methyl acetate and isopropyl acetate; alcohols such as n-butanol; ketones such as methyl isobutyl ketone (MIBK); ethers such as di-ethyl ether, di-isopropyl ether, di-methyl ether and methyl tertiary butyl ether; cyclic ether such as 2-methyltetrahydrofuran; or mixtures thereof.
30. The process as claimed in claim 1, wherein the base used step (iia) for basification and the base used in step (va) for washing is selected from inorganic bases such as ammonium
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hydroxide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, calcium bicarbonate and ammonium bicarbonate; and organic bases selected from triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine and pyridine and their mixtures thereof.
31. The process as claimed in claim 1, wherein the second solvent used in step (via) is selected from alcohols such as methanol, ethanol, isopropanol and n-butanol; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbon such as dichloromethane and dichloroe thane; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate and isopropyl acetate; water or a mixture thereof.
The process as claimed in any of the preceding claims, wherein the compound of formula (XIV) and (XlVa) used in the step (c) can be optionally obtained by
reacting a compound of formula (II) with a compound of formula (III) or its acid addition salt of compound of formula (Ilia) in presence of a solvent; optionally in presence of a base and/or catalyst to obtain compound of formula (XIV); and optionally converting it into its acid addition salt of formula (XlVa).
33. The process as claimed in claim 32, wherein the solvent used in step (f) is selected from alcohols such as methanol, ethanol, isopropanol and n-butanol; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbon such as dichloromethane and dichloroethane; formamide such as N,N-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethylsulfoxide; cyclic amides such as N-Methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate and isopropyl acetate; water; ionic liquids; or a mixture thereof.
34. The process as claimed in claim 32, wherein the base used in step (f) may be organic or inorganic base; the organic bases such as l,8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as methylamine, propyl amine, 2- propyl amine and butyl amine; secondary amines such as Ν,Ν-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine and morpholine; tertiary amines such as triethylamine, Ν,Ν-dimethyl aniline, Ν,Ν-diisopropyl ethyl amine and trimethyl amine; pyridine or substituted pyridine such as 2,6-lutidine, 2,4-lutidine and 3,5-lutidine; pyrimidine and Ν,Ν-dimethylethyl amine; tetra alkyl ammonium and phosphonium hydroxides; metal alkoxides and inorganic bases such as alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; metal hydrides; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert butoxide; metal amides or liquor ammonia.
35. The process as claimed in claim 32, wherein the catalyst used in step (f) is selected from organic, inorganic catalyst, or phase transfer catalyst, optionally in the presence of acids such as Lewis acid.
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36. The process as claimed in claim 32, wherein the step (f) further comprises isolation of the compound of formula (XIV) or its acid addition salt of compound of formula (XIV a); the said process comprises the steps of:
ic. treating the reaction mass of step (f) with water;
iic. extracting the aqueous layer of step (ic) with an organic solvent;
iiic. separating the organic layer of step (iic) followed by washing it with base and brine; ivc. concentrating the organic layer of step (iiic) to obtain the compound of formula (XIV); and
vc. optionally acidifying the organic layer obtained in step (ivc) to precipitate the acid addition salt of compound of formula (XlVa), filtering the precipitate, and washing it with organic solvent followed by drying it to obtain compound of formula (XlVa).
37. The process as claimed in claim 36, wherein the organic solvent used in step (iic) is selected from the group comprising of aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptanes; halogenated hydrocarbons such as dichloromethane; carboxylic acid esters such as ethyl acetate, methyl acetate and isopropyl acetate; ethers such as di-ethyl ether, di-isopropyl ether, di-methyl ether and methyl tertiary butyl ether; substituted cyclic ether such as 2-methyl tetrahydrofuran; or mixtures thereof.
38. The process as claimed in claim 36, wherein the base used step (iiic) for washing is selected from inorganic bases such as ammonium hydroxide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, calcium bicarbonate and ammonium bicarbonate; and organic bases selected from triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine and pyridine and their mixtures thereof.
39. The process as claimed in claim 36, wherein the acid used in step (vc) for acidification is selected from organic or inorganic acids such as hydrochloric acid, hydrobromic acid,
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sulfuric acid, formic acid, acetic acid, oxalic acid, isopropyl alcohol hydrochloride solution and ethyl acetate hydrochloride solution.
40. The process as claimed in claim 36, wherein the organic solvent for washing used in step (vc) is selected from the group comprising of aliphatic hydrocarbons such as hexane and heptanes; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane and dichloroe thane; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, methyl acetate and isopropyl acetate; nitriles such as acetonitrile and propionitrile; ethers such as di-methyl ether, di-ethyl ether, di-isopropyl ether and methyl tertiary butyl ether; cyclic ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol and isopropyl alcohol; chloroform; or mixture thereof.
41. The process as claimed in any of the preceding claims, wherein the Mirabegron of formula (I) prepared by foregoing process can be purified by providing solution in alcohols such as 2-propanol and n-butanol; hydrocarbons such as hexane, n-heptane, toluene and xylene; or mixture thereof; cooling the solution; filtering and drying the solid to obtain pure a-crystalline form of Mirabegron of formula (I).
42. The process as claimed in any of the preceding claims, wherein the a-crystalline form of Mirabegron prepared by foregoing process has purity more than 99%; preferably more than 99.5% when determined by HPLC.
43. The process as claimed in any of the preceding claims, wherein optionally the compound of formula (XIV), (XV) and Mirabegron of formula (I) can be converted to their corresponding acid addition salt of formula (XlVa), (XV a) and (la); wherein the acid addition salt may be mono, di- or tri- acid salt; said salts includes such as acetate, hydrochloride, sulfate, oxalate, bromide, succinate, trifluoroacetate, lactate, malonate, glutarate, glutamate, citrate, ascorbate, camphor sulfonate, pamoate, pyruvate, maleate, tosylate, formate, tartarate, mesylate, oxalate, fumarate, phosphate and dimesylate.
69
The process as claimed in any of the preceding claims wherein the Mirabegron and a- crystalline form thereof prepared by foregoing process, having less than about 0.2% of compound of formula (A), less than about 0.2% of compound of formula (B), less than about 0.2% of compound of formula (C), less than about 0.2% of compound of formula (D), less than about 0.2% of compound of formula (E), less than about 0.2% of compound of formula (F), less than about 0.2% of compound of formula (G), less than about 0.2% of compound of formula (H), less than about 0.2% of compound of formula (I), less than about 0.2% of compound of formula (J), less than about 0.2% of compound of formula (K), less than about 0.2% of compound of formula (L), less than about 0.2% of compound of formula (M), less than about 0.2% of compound of formula (N), less than about 0.2% of compound of formula (O), less than about 0.2% of compound of formula (P), less than about 0.2% of compound of formula (Q), less than about 0.2% of compound of formula (R), less than about 0.2% of compound of formula (S), less than about 0.2% of compound of formula (T), less than about 0.2% of compound of formula (U),less than about 0.2% of compound of formula (V),less than about 0.2% of compound of formula (W),less than about 0.2% of compound of formula (X) and less than about 0.2% of compound of formula (Y);
71
Statement under Article 19
This has the reference of PCT/IS A/220 with respect to PCT/IN2014/000637. Our comments on the basis of amendments are as under:
The current invention relates to process for preparation of a-crystalline form of Mirabegron reacting 4-nitrophenylethylamine or its acid addition salt with (i?)-mandelic acid in presence of a solvent and reagent, optionally in presence of base, and/or catalyst to obtain (i?)-2-hydroxy-N-[2- (4-nitrophenyl)ethyl]-2-phenylacetamide; reducing (i?)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2- phenylacetamide in presence of reducing agent and a solvent to obtain (i?)-2-[2'-(4- nitrophenyl)ethyl]amino]-l-phenylethanol, optionally converting it into its acid addition salt; reducing (i?j-2-[2'-(4-nitrophenyl)ethyl]amino]-l-phenylethanol or its acid addition salt in solvent to obtain (i?)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol or its acid addition salt respectively; reacting compound (i?)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol or its acid addition salt with 2-aminothiazole-4-yl-acetic acid in the presence of solvent, acid and a condensing agent, optionally in the presence of a catalyst to obtain Mirabegron; and Isolating a-crystalline form of Mirabegron of formula (I) obtained in step (d) by ia) adding first solvent to the reaction mass of step (d), iia)basifying the solution of step (ia) and optionally heating the reaction mixture, iiia) separating the organic layer, iva)extracting the aqueous layer with solvent, and combining the obtained organic layer with organic layer of step (iiia), va) washing the combined organic layer with aqueous base followed by water, separating the organic layer and optionally distilling the organic layer, and via)adding second solvent to organic layer of step (va) to obtain α-crystalline form of Mirabegron.
The inventive step of the present invention lies in the isolation of α-crystalline form of Mirabegron and avoiding neutralization of the mass at step (d) and eliminates the formation of β- crystal form. The present invention adds the first solvent after step (d) and then basify the reaction mass which avoids crystallization of β-crystal of Mirabegron as Mirabegron dissolved and remained in the organic layer, α-crystalline form of Mirabegron is obtained by distilling the organic solvent or by adding second solvent to the organic layer or by cooling organic layer. 72
Thus, we have clubbed claim 28 with claim 1 and now amended claim 1 clearly bring out inventive step as well as clearly states how the present invention directly yields a-form of Mirabegron. This eliminates need of conversion of β-form into a-form and results into direct isolation of a form thereby making the process simple and efficient. The present invention also does not require alpha form crystals for seeding thereby making the process robust. Therefore, claims 1 -45 are inventive.
The specification including examples 1-9 and amended claims clearly disclosed and demonstrated the present invention including the isolation of a-form of Mirabegron.
According to Sec. 6, we have deleted terms like "But not limited to"; "like" and "and the like" from claim nos. 2 to 4, 6 to 9, 12 to 15, 17 to 20, 22, 24 to 27, 29 to 31, 33 to 35, 37 to 41 and 43.
We have renumbered original claim nos 29 to 45 as claim nos 28 to 44. We have also amended dependancy of the claims 28 to 44 as required.
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| IN3116/MUM/2013 | 2013-09-30 | ||
| IN826MU2014 | 2014-03-12 | ||
| IN826/MUM/2014 | 2014-03-12 | ||
| IN3116MU2013 IN2013MU03116A (en) | 2013-09-30 | 2014-09-30 |
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| WO2016049749A1 (en) * | 2014-10-01 | 2016-04-07 | Apotex Inc. | Solid forms of mirabegron |
| CN105111165B (en) * | 2015-09-14 | 2017-10-31 | 保定博洋生物科技有限公司 | A kind of preparation method of Mirabegron |
| CN106278909B (en) * | 2016-08-12 | 2022-07-15 | 浙江华海药业股份有限公司 | Post-treatment method of mirabegron intermediate |
| EP3335700A1 (en) | 2016-12-13 | 2018-06-20 | Stada Arzneimittel Ag | Solid pharmaceutical oral dosage form comprising an extended release of the active ingredient comprising mirabegron |
| CZ2017461A3 (en) * | 2017-08-09 | 2019-02-20 | Saneca Pharmaceuticals A.S. | Method of preparing 4-nitrophenylethylamide of mandelic acid from 4-nitrobenzylcyanide |
| CN108658797A (en) * | 2018-06-19 | 2018-10-16 | 安徽德信佳生物医药有限公司 | A kind of synthesis of Mirabegron intermediate (R) -2- (4- nitrophenethyls amino) -1- phenylethanol hydrochlorides |
| CN109456277B (en) * | 2018-10-29 | 2022-04-22 | 安徽省庆云医药股份有限公司 | Preparation method of mirabegron |
| CN109651290B (en) * | 2018-10-31 | 2022-04-01 | 安徽省庆云医药股份有限公司 | Preparation method of mirabegron |
| KR20200117091A (en) * | 2019-04-02 | 2020-10-14 | 제이투에이치바이오텍 (주) | Prodrug compound of mirabegron and its medical use for treating or alleviating overactive bladder diseases |
| CN112725389B (en) * | 2019-10-29 | 2023-07-18 | 广东东阳光药业有限公司 | Preparation method of mirabegron intermediate |
| CN111072589B (en) * | 2019-12-25 | 2022-03-22 | 北京振东光明药物研究院有限公司 | Recrystallization method and preparation method of mirabegron |
| CN111302966A (en) * | 2020-04-03 | 2020-06-19 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of mirabegron intermediate |
| CN113816864B (en) * | 2020-06-18 | 2024-03-29 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenethylamine |
| CN113773274A (en) * | 2021-08-09 | 2021-12-10 | 石药集团中奇制药技术（石家庄）有限公司 | Recrystallization method of mirabegron alpha crystal form raw material |
| CN116459857B (en) * | 2023-04-24 | 2024-04-19 | 安徽大学 | High-selectivity catalyst Co/NS800, preparation method thereof and method for selectively hydrogenating p-chloronitrobenzene in heterogeneous system |
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| US7342117B2 (en) | 2001-10-30 | 2008-03-11 | Astellas Pharma Inc. | α-form or β-form crystal of acetanilide derivative |
| US9283210B2 (en) | 2011-05-18 | 2016-03-15 | Dr. Reddy's Laboratories Ltd. | Amorphous mirabegron and processes for crystal forms of mirabegron |
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