WO2015155664A1

WO2015155664A1 - An improved process for the preparation of 2-(2-aminothiazol-4-yl)-n-[4-(2-[[(2r)-2-hydroxy-2- phenylethyl]amino]-ethyl)phenyl]acetamide

Info

Publication number: WO2015155664A1
Application number: PCT/IB2015/052478
Authority: WO
Inventors: Rajendiran Chinnapillai; Indrasena Reddy KONDAKINDI; Venkateswarlu Jasti
Original assignee: Suven Life Sciences Limited
Priority date: 2014-04-08
Filing date: 2015-04-06
Publication date: 2015-10-15

Abstract

The present invention relates to an improved process for the preparation of pure 2-(2- amino-1,3-thiazol-4-yl)-N-[4-(2-[(2R)-2-hydroxy-2-phenylethyl]amino]ethylphenyl]- acetamide of formula (1) substantially free of impurities. The present invention relates to the novel process of preparing intermediate (R)-1- Phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol hydrochloride of formula (2) in high yield, which is useful in the preparation of mirabegron of formula (1). The process also relates to the preparation of pure α –form crystal of 2-(2-Amino- 1,3-thiazol-4-yl)-N-[4-(2-[(2R)-2-hydroxy-2-phenylethyl]amino]ethylphenyl]acetamide Mirabegron (1) without isolation of β-form.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF 2-(2-AMINOTHIAZOL-4-YL)-N-[4-(2-[[(2R)-2-HYDROXY-2- PHENYLETHYL]AMINO]-ETHYL)PHENYL]ACETAMIDE

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of compound 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]- ethyl)phenyl]acetamide of formula (1).

BACKGROUND OF THE INVENTION

Mirabegron (formerly YM- 178) is an orally active β-3 adrenoceptor agonist developed by Astellas pharma for the potential treatment of urinary frequency, urinary incontinence, or urgency associated with overactive bladder. Mirabegron is approved in several countries and available in the market under the brand names Myrbetriq in US, as Betmiga in (EU) and as Betanis in Japan as Extended Release Tablets in the strengths of 25 and 50mg.

Mirabegron is chemically described as 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2- hydroxy-2-phenylethyl] amino] -ethyl )phenyl]acetamide and additionally as 2-amino-N-[4- [2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethylphenyl]-4-thiazoleacetamide and represented by structural formula (1). (which is hereafter referred either by Mirabegron or by its chemical name as required).

(1) DESCRIPTION OF THE RELATED ART

U.S. Patent No. 6,346,532 describes novel amide derivatives or salts thereof including Mirabegron. The said patent discloses the synthesis of mirabegron as dihydrochloride salt of formula (7) and related compounds by using different methods. One of the method disclosed for the synthesis of Mirabegron dihydrochloride salt of formula (7) is illustrated by below scheme- 1.

Scheme- 1

Briefly, the above process for the preparation of mirabegron dihydrochloride of formula (7) involves reaction of (R)-styrene oxide of the formula (3) with 4-nitrophenyl ethylamine hydrochloride of the formula (4) in IPA at reflux temperature for 12 hrs then purified by silica gel column chromatography and then reacted with Boc anhydride, followed by silica gel column chromatography purification to give pure compound of the formula (5). Further compound of the formula (5) hydrogenated with Pd/C followed by reaction with 2- aminothiazol-4-yl-aceticacid of formula (6) and further treatment with MeOH/HCl gives Mirabegron dihydrochloride of formula (7).

The process disclosed in the above patent US'532 have several drawbacks particularly as it cannot be adapted on commercial scale for example use of high cost (R)- styrene oxide, lower yield (about 22%) particularly in the coupling of (R)-styrene oxide of the formula (3) with 4-nitrophenyl ethylamine hydrochloride of the formula (4), silica gel column purification, and protection, deprotection steps.

U.S. Patent No. 7,342, 117B2 discloses a and β crystals forms Mirabegron and processes thereof, which is depicted by below scheme-2. ding

(1)

Scheme-2

The process comprises the reaction of (R)-mandelic acid of formula (8) with 4- nitrophenylethylamine (monohydrochloride or ½ sulfate) of formula (4) in the presence of hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride in Ν,Ν-dimethylformamide as solvent to yield (R)-2-hydroxy-N-[2-(4-nitrophenyl)- ethyl]-2-phenylacetamide of formula (9), which is further reacted with 1M borane- tetrahydrofuran solution in l,3-dimethyl-2-imidazolidinone and tetrahydrofuran at -18°C followed by hydrogenation in presence of 10% palladium-carbon and hydrogen atmosphere to yield (R)-2-[[2-(4-aminophenyl)ethyl] amino] - 1 -phenylethanol monohydrochloride of formula (10). Further (R)-2-[[2-(4-aminophenyl)ethyl] amino] -1 -phenylethanol monohydrochloride of formula (10) coupled with 2-aminothiazol-4-yl-aceticacid of formula (6) in presence of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride to yield beta-crystal form of Mirabegron of formula (11), which is further converted into alpha-crystal form of Mirabegron of formula (1) in aqueous ethanol by dissolving at 80°C followed by seeding with alpha- crystal form of Mirabegron of formula (1).

The process disclosed in the above said patent US '117 for the preparation of a crystal form of Mirabegron of formula (1) has several drawbacks particularly of commercial applicability for example use of highly hazardous chemicals like 1M borane-tetrahydrofuran solution and solvents like Ν,Ν-dimethylformamide, l,3-dimethyl-2-imidazolidinone, low temperature (-18°C) reaction, formation of β-form and further conversion into stable a- form of Mirabegron of formula (1) using aqueous ethanol, therefore the process is not suitable for commercial scale. Aforementioned reported processes for the preparation of Mirabegron of formula ( 1 ) have several drawbacks namely,

(i) . use of hazardous chemicals like 1M borane-tetrahydrofuran.

(ii) . protection and deprotection steps, which leads to increase in number of steps and low

yield.

(iii) . use of expensive chemical like (R)-Styrene oxide.

(iv) . silica gel chromatography purification, which is industrially not feasible for commercial purpose.

(v) . formation of β-form crystal and further conversion into a-form crystal, which leads to multiple number of process steps.

Purity of the active compound is an extremely important parameter specifically for products used as APIs (active pharmaceutical ingredients). Various grades of purity of the same product are possible at the end of the production process. In general, the purity of the product depends on the chemistry and various process related parameters of the production process. In the case of peptide products the situation is even more complicated as peptides are complex and sensitive molecules. They are produced by multi-step processes applying an extensive variety of starting materials and are potentially contaminated due to the many possible side reactions, which are part of synthetic chemistry.

Thus, it is the object of the present invention to devise other improved methods of synthesizing the Mirabegron that lacks the disadvantages of the prior art.

Hence, there is a need to provide an improved process for the preparation of Mirabegron (1), which avoids the use of potential hazardous and expensive chemicals, formation of isomeric and other process related impurities, while affording the desired product Mirabegron with high yield and purity.

The present invention provides an improved process for the synthesis of highly pure Mirabegron of formula (1) devoid of aforementioned drawbacks of the reported processes.

The process of the present invention is simple, eco-friendly, economic, reproducible, robust and well amenable on commercial scale. OBJECTIVES OF THE PRESENT INVENTION

A study has been undertaken by the present inventors for the synthesis of Mirabegron of formula (1) by reacting (R)-styrene oxide of formula (3) with 4-Nitrophenylethymine of formula (4), the inventors have found during this reaction, the product yield was very low (about 22%). To overcome the yield and optimize the reaction conditions, initiative has been taken to investigate the cause for this lower yield, and found there were four products forming in this reported reaction conditions including the required compound of the formula (2). The other three products which are identified and designated as (R)-2-[2-(4-Nitro- phenyl)-ethylamino]-2-phenyl-ethanol impurity-A (at RRT:0.98 with a level of 8-10%, (R)- 2-[(2-hydroxy- 1 -phenyl-ethyl)-[2-(4-nitro-phenyl)-ethyl] -amino] - 1 -phenyl -ethanol impurity- B at RRT.1.31 with a level of 5-8% and (R)-2-[(2-hydroxy-2-phenyl-ethyl)-[2-(4-nitro- phenyl)-ethyl] -amino] -1-phenyl-ethanol impurity-C at RRT.1.35 with a level of 25-30% as determined by HPLC .

Impurity-A Impurity-B Impurity-C

Multiple purifications or multiple column purifications were required to eliminate these potential impurities namely (R)-2-[2-(4-Nitro-phenyl)-ethylamino]-2-phenyl-ethanol impurity-A, (R)-2-[(2-Hydroxy-l-phenyl-ethyl)-[2-(4-nitro-phenyl)-ethyl]-amino]- 1-phenyl- ethanol impurity-B and (R)-2-[(2-Hydroxy-2-phenyl-ethyl)-[2-(4-nitro-phenyl)-ethyl] -amino] -

1- phenyl-ethanol impurity-C. If these potential impurities were not eliminated completely, these will carry over to final stage resulting in corresponding mirabegron derivatives as (R)-2- (2-Amino-thiazol-5-yl)-N-[4-[2-(2-hydroxy-l-phenyl-ethylamino)-ethyl]-phenyl]-acetamide impurity-Al, (R)-2-(2-Amino-thiazol-5-yl)-N-(4-[2-[(2-hydroxy-l-phenyl-ethyl)-(2-hydroxy-

2- phenyl-ethyl)-amino] -ethyl] -phenyl)-acetamide impurity-B 1 and (R)-2-(2-Amino-thiazol-5- yl)-N-(4-[2-[bis-(2-hydroxy-2-phenyl-ethyl)-amino]-ethyl]-phenyl)-acetamide impurity-Cl at RRT: 1.05, 1.52, 1.58 respectively which are determined by HPLC which are formed during the preparation of Mirabegron of formula ( 1 ) thus leading to lower yields and impure form of Mirabegron of formula (1).

Impurity- A 1 Impurity-B l

Impurity-C 1

In view of the aforementioned drawbacks and keeping in view of the importance of this product there is a need for an efficient and industrial applicable process for the synthesis of Mirabegron of formula (1) which can completely arrests the formation of impurities A, B, C, Al, B l, and CI thus leading to afford mirabegron with high yield and purity.

The principle object of the present invention is to provide an improved process for the preparation of compound Mirabegron of formula (1) using the intermediate compound 2.

(2) Another object of the present invention is to provide a novel process for the synthesis of compound (R)-l-Phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol hydrochloride of formula (2), an intermediate in the synthesis of mirabegron of formula (1) by employing readily available and easy to handle reagents.

Another object of the present invention is to provide Mirabegron of formula (1) substantially free from aforementioned impurities.

A further object of the present invention is to provide a process for the synthesis of pure a - crystal form of Mirabegron of formula (1) without isolation of β-crystal form.

A further object of the present invention is to provide an improved process for the preparation of compound Mirabegron of formula (1) avoiding the use of hazardous chemical 1M borane-tetrahydrofuran.

Still another object of the present invention is to provide an improved process for the preparation of compound Mirabegron of formula (1) avoiding silica gel purification.

A further object of the present invention is to provide an improved process for the preparation of Mirabegron of formula ( 1 ) which can be readily adopted on commercial scale.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of pure compound2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl] amino] - ethyl )phenyl]-acetamide of formula (1).

The present invention also relates to a novel process for preparing (R)-l-phenyl-2- [[2-(4-nitrophenyl)ethyl] amino] ethanol hydrochloride of formula (2), which is useful as an intermediate in the synthesis of mirabegron of formula (1).

In one aspect, the present invention provides an improved process for the preparation of pure 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]- amino] ethyl )phenyl]acetamide of formula (1)

(1)

comprising the steps of : (a) reacting the compound (R)-(-)-l-phenyl-l,2-ethanediol 2-tosylate of formula (12),

(12 )

a compound 4-nitrophenylethylamine of formula (13 ),

(13)

in the presence of suitable organic solvent to afford a compound of formula (2)

(2)

b) subjecting the compound of formula (2) to catalytic hydrogenation using suitable catalyst in the presence of solvent to afford a compound of formula (10)

(10)

c) reacting the compound of formula (10 ) with a compound 2-aminothiazol-4-acetic acid of formula (6)

in the presence of suitable catalyst and a solvent to afford pure compound 2-(2- aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl)phenyl]- acetamide of formula (1).

In another aspect, the present invention provides 2-(2-aminothiazol-4-yl)-N-[4-(2- [[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl)phenyl]acetamide of formula (1) having the impurities namely A, B, C, Al, Bland CI less than about 0.1% by wt. as determined by chiral HPLC.

In yet another aspect, the present invention provides Mirabegron (1) having chemical purity greater than about 99.5% by wt. as measured by HPLC and chiral purity greater than about 99.8% by wt. as measured by chiral HPLC.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of pure compound2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl] amino] - ethyl )phenyl]acetamide of formula (1).

In one embodiment, the present invention provides an improved process for the preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]- ethyl)phenyl]acetamide of formula (1)

(1)

comprising the steps of:

a) reacting the compound (R)-(-)-l-phenyl-l,2-ethanediol 2-tosylate of formula (12),

(12 ) with a compound 4-nitrophenylethylamine of formula (13 ),

(13)

in the presence of suitable organic solvent to afford a compound (R)-l-Phenyl-2-[[2- (4-nitrophenyl)ethyl] amino] ethanol hydrochloride of formula (2)

(2)

b) subjecting the compound of formula (2) to catalytic hydrogenation in the presence of suitable catalyst and solvent to afford the compound (R)-l-Phenyl-2-[[2-(4- aminophenyl)ethyl]amino]ethanol monohydrochloride of formula (10)

(10) c) reacting the compound of formula (10 ) with a compound 2-aminothiazol-4-acetic acid of formula (6)

in the presence of suitable catalyst and a solvent to afford the pure compound 2-(2- aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl)phenyl]- acetamide of formula (1).

The suitable organic solvent that can be used in step (a) is selected from group consisting of tetrahydrofuran (THF), 2-methyl THF, methyltertiarybutylether (MTBE), acetonitrile, 2-propanol, toluene or mixture thereof, preferably tetrahydrofuran (THF) is being used.

The volume of the solvent used in the reaction step (a) can be in the range from about 0 to about 10 volumes; preferably about 1 to about 3 volumes. However there is no limitation for the volume of the solvent(s) or mixture of solvents being used.

Optionally the reaction step (a) is carried out in the presence of a base which can be selected from organic or inorganic base. Preferably the reaction is carried out in the absence of base.

The suitable base that is being used optionally for basification include but not limited to organic bases such as triethylamine, diisopropylethylamine, pyridine and the like; Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate; sodium hydroxide, ammonium hydroxide and the like or mixture thereof; preferably sodium hydroxide.

The molar equivalent of compound of formula (13) used in the reaction can be in the range from about 1 to about 3.5 molar equivalents, preferably 2 to 3 molar equivalents is being used.

Optionally the reaction is performed in the absence of solvents.

The reaction step (a) is carried out at a temperature from about 0°C to about reflux temperatures of the solvent(s) used, preferably about 60°C.

The time period required for the reaction to complete may vary depending upon the reaction temperature, the nature of the reagents and solvents employed. The time period required for the reaction step (a) to complete can range from about 10 to about 20 hours, preferably a period from about 15 to about 20 hours is sufficient.

The suitable catalyst that can be employed in step (b) is selected from the group consisting of raney nickel, palladium on carbon, palladium hydroxide, iron powder, Zinc dust and stannous chloride or a mixture thereof in combination with metal, preferably palladium on carbon, raney nickel and iron powder, more preferably raney nickel in the presence of hydrogen gas is being employed.

The reaction step (b) can be carried out using customary reducing agents which is devoid of use of hydrogen gas.

The suitable solvent that can be used in step (b) is selected from group consisting of methanol, ethanol, ethyl acetate, 2-propanol, water or mixture thereof, preferably methanol and ethyl acetate, more preferably methanol is being used.

The volume of the solvent used in the reaction step (b) can range from about 5 to 30 volumes, more preferably 12 to 15 volumes. However, there is no limitation for the volume of the solvent(s) being used.

The reaction step (b) is carried out at a temperature from about 25 to about 60°C, preferably from about 40°C to about 45°C.

The time period required for the reaction to complete may vary depending upon the reaction temperature, the nature of the reagents and solvents employed.

The reaction time for the reaction step (b) can range from about 6 hours to about 10 hours. Preferably a period of about 8 hours is sufficient.

The suitable catalyst that can be used in the reaction step (c) can be a conventional coupling agent selected from the group consisting of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide mono hydrochloride, N,N'-dicyclohexylcarbodiimide, hydroxybenzotriazole (HOBt), 2-(lH-benzotriazole-l-yl)-l, l,3,3-tetramethyluronium tetrafluoroborate (TBTU), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium-3-oxidohexafluorophosphate (HATU), benzotriazol- 1 -yl-oxytripyrrolidino- phosphonium hexafluorophosphate (PyBOP), benzotriazol- l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate (BOP), or mixture thereof; preferably the coupling agent l-(3-dimethylaminopropyl)-3-ethylcarbodiimide mono hydrochloride is being used. The molar equivalents of coupling agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide mono hydrochloride being used can range from about 1 to about 2.5 molar equivalents; preferably from about 1 to about 1.6 molar equivalents is being sufficient.

The suitable solvent that can be used in reaction step (c) is selected from group consisting of acetonitrile, tetrahydrofuran (THF), dichloromethane (DCM), 2-methyl THF, methyl tertiary butyl ether (MTBE), 2-propanol, toluene, and water or mixture thereof; preferably a mixture of acetonitrile and water is being used in any proportion without limitation.

Optionally, the reaction step (c) is carried out in the presence of an acid which include inorganic or organic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesufonic acid, trichloroacetic acid, trifluoroaceticacid or mixture thereof; preferably the acid being used is hydrochloric acid.

The molar equivalents of compound of formula (6) being used in the reaction can be in the range from about 1 to about 2 molar equivalents, preferably from about 1 to about 1.12 molar equivalents is being sufficient.

The reaction step (c) is carried out at a temperature range from about 5°C to about 30°C; preferably from about 20°C to about 30°C.

The time period required for the reaction to complete may vary depending on the reaction temperature, the nature of the reagents and solvents employed.

The time period for the reaction step (c) to accomplish can range from about 2 hours to about 8 hours; preferably from about 4 to 5 hours are being sufficient.

The isolation of pure a- form crystal of compound of formula (1) is achieved at a temperature ranging from about 0°C to about 30°C; preferably from about 5°C to about 10°C.

The time period required for the isolation of pure a-form crystal of compound of formula (1) may range from 2 to 20 hours preferably 10 to 15 hours.

Advantageously the above described process of present invention provides a pure a- form crystal of 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]- ethyl)phenyl]acetamide of formula (1) which is without isolation of β-form crystal. The pure a-form crystal of mirabegron (1) obtained by the process of present invention is substantially in accordance with the XRPD and DSC of mirabegron a-form crystal disclosed in US 7,342,117B2.

After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional techniques known in the art.

For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.

Recovery or isolation of Mirabegron ( 1 ) and its intermediates obtained herein by the process of present invention can be achieved by any conventional methods known in the art, for example filtration or centrifugation.

In one embodiment, mirabegron (1) and its intermediates obtained herein by the process of present invention may further dried that can be at a temperature range from about 30°C to about 50°C in the presence or absence of vacuum, preferably from about 30°C to about 45°C.

Optionally the process steps of present invention can be carried out by one pot synthesis.

Advantageously the intermediates or their salts used here in the processes of the present invention may exist in either crystalline or amorphous or mixtures thereof and can exist in any salt form.

The starting compounds and intermediate compounds that are being used herein the process of present invention can be prepared from any of the processes reported in the literature.

The starting compound of formula (12) used herein is obtained from (R)-(-)-l- phenyl-l,2-ethanediol by using process reported in the US application publication US 20040110985A1.

In another embodiment, the present invention provides the compound 2-(2- aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl)phenyl]- acetamide of formula (1) having the impurities namely A, B, C, Al, Bland CI less than about 0.1% by wt. as determined by chiral HPLC.

Impurity-A Impurity-B Impurity-C

In yet another embodiment, the present invention provides Mirabegron (1) having chemical purity greater than about 99.5% as measured by HPLC and chiral purity greater than about 99.8% as measured by chiral HPLC.

Advantages of the present invention: The above described improved process for preparation of 2-(2-aminothiazol-4-yl)-N- [4-(2-[[(2R)-2-hydroxy-2-phenylethyl] amino] ethyl )phenyl]acetamide (Mirabegron) of formula (1) has following advantages:

(i) . The process does not involve the use expensive chemical like (R)-styrene oxide,

thus the process is economic and cost-effective.

(ii) . The process does not involve Silica-gel chromatographic purification to obtain pure 2-

(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl)phenyl]- acetamide of formula (1) thus the process can be well adopted on commercial scale.

(iii) . The process does not involve the use of hazardous chemical like 1M borane- tetrahydrofuran, and hence the process is ecofnendly and easy to handle on commercial scale.

(iv) . The process uses readily and commercially available low cost, non toxic

chemicals and thus the process is safe and economic.

(v) . The process provides pure a -crystal form of 2-(2-aminothiazol-4-yl)-N-[4-(2- [[(2R)-2-hydroxy- 2-phenylethyl] amino] ethyl )phenyl]acetamide (Mirabegron) of formula (1) without the isolation of β-form. Thus the process is simple and improved.

(vi) . The compound of formula (13) being used in excess is recoverable and reusable, thus the process is economic.

(vii) The process provides the compound 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2- hydroxy-2-phenylethyl] amino] -ethyl)phenyl]acetamide of formula (1) substantially free of impurities A, B, C, Al, B land CI respectively.

The processes reported in the literature for the preparation of Mirabegron (I) or its intermediates in the art results in the formation of various impurities and bye products leading to include additional purification steps at several stages thus resulting in very poor yields and purities of the final product.

Advantageously, the process of present invention does not involve purification steps thus provides the final product Mirabegron (l)with high yield and purity.

Preferably, the yield of the intermediates and the final product is greater than about 70%, or more, more preferably, the yield is greater than about 75%, most preferably, the yield is greater than about 80%, or more, by weight. The product obtained by the process described above can have high enantiomeric excess. Preferably, the amount of S-enantiomer is less than about 1% as measured by area percentage by chiral HPLC, more preferably less than about 0.5%, and most preferably less than about 0.1% by chiral HPLC.

The process according to the present invention preferably yields Mirabegron (1) in substantially pure enantiomeric form. Thus the ratio of (R) : (S) as obtained by the process of present invention may be at least about 99: 1, such as at least about 99.8:0.2, or more preferably at least about 99.9 : 0.1. Preferably Mirabegron prepared by a process according to the present invention has an enantiomeric purity of at least about 99.5%, or more preferably at least about 99.9 area% as determined by chiral HPLC.

Analytical test methods:

IR spectra were recorded on Perkin Elmer Spectrophotometer as KBr pellets or neat.

1 H-NMR and 1¹3^JC-NMR spectra were recorded on a Bruker 400 MHz spectrometer with

TMS as internal standard (chemical shift in δ, ppm) and mass spectra were measured on API 4000 model.

HPLC method to determine the chemical purity of Mirabegron (1).

Column: Octyl silyl silica gel (L3 packed), 250x4.6 mm, 5μιτι. Eluent-A: Water pH adjust

3.0 with Orthophosphoric acid; Eluent-B: Methanol; Gradient programme [time / %B]: 0 / 2;

22 / 50; 25 / 90; 35 / 90; 35.1 / 2; 40 / 2; l.OmL/min, 25°C, Inj. νο1:5.0μΕ; detector: 210 nm, Con=0.4 mg/mL in H₂0:ACN [1: 1], t_r=11.95 min.

Chiral HPLC method to determine the chiral purity of Mirabegron (1).

Column: Chiral Pak IF-3; 30% n-Hexane, 30% MTBE, 40% MeOH, 0.1% DEA; l.OmL / min, 25°C, Inj. νο1: 10.0μΕ; detector: 250 nm, Con=0.2 mg/mL in diluent mobile phase, t,=10.6 min, t_r=9.4 min (isomer),

The present invention provides simple, ecofriendly, inexpensive, reproducible, robust process for preparation of Mirabegron (I) and its intermediate compound of formula

(2) which are amenable on commercial scale.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended within the scope of the present invention. The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.

Examples

Example-1: Preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2- phenyl ethyl]amino]-ethyl)phenyl]acetamide of formula (1)

Step (I): Preparation of (R)-l-Phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol

(12) (13) (2)

100.0 gm (0.342 mol) of (R)-(-)-l -phenyl- 1,2-ethanediol 2-tosylate of formula (12) and 170.6 gm (1.026 mol) of 4-nitrophenylethylamine of formula (13) and 300ml of tetrahydrofuran (THF) were charged in a clean and dry round bottom flask and stirred. The resultant reaction mixture was heated to about 60°C and stirred for about 18 hours. The reaction progress was monitored by TLC, after completion of reaction, reaction mass was cooled to about 30°C. The solid precipitated was filtered and the solid was washed with 200ml of tetrahydrofuran (THF). The filtrates were combined and distilled off under reduced pressure to afford the syrup. The resultant syrup was suspended in 300ml of methyl tertiary butyl ether (MTBE) and treated with 13% w/w (144.2 gm (0.513 mol) of IPA/HC1 (HCl gas suspended in isopropyl alcohol) for about 1 hour at about 25-35°C. The separated solid was filtered and the solid was washed with MTBE followed by slurry wash with water. The solid obtained was dried till to get constant weight to yield 70 gms of (R)-l-Phenyl-2-[[2-(4- nitrophenyl)ethyl]amino]ethanol hydrochloride of formula (2) as crystalline solid. M.P: 194.1-197.4°C; SOR: [a]²⁵: -35° (c=0.5 in MeOH);

FTIR (KBr): 3542, 2990, 2442, 1607, 1598, 1522, 1441, 1347, 1315, 1272, 1070, 1026, 991,932, 851, 702 cm^"1 ^XH-NMR (400 MHz, DMSO-d₆): δ (ppm) = 2.99-3.07 (m, 1H), 3.15-3.24 (m, 5H), 5.05 (d, 1H), 6.24 (s, 1H), 7.28-7.40 (m, 5H), 7.54 (d, J=8.2 Hz, 2H), 8.16 (d, J=8.2 Hz, 2H), 9.4 (br s, 2H); ¹³C-NMR (400 MHz, DMSO-d₆): δ (ppm)= 31.4, 47.5, 53.9, 68.5, 123.9, 126.2, 128.0, 128.6, 130.4, 142.1, 146.0, 146.7; MS: m/z=287 (M+H)⁺.

Step (II): Preparation of (R)-l-Phenyl-2-[[2-(4-aminphenyl)ethyl]amino]ethanol

monohydrochloride of formula (10)

(2) (10)

Method-(a): 88.0 gm of (R)-l-Phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol hydrochloride of formula (2) obtained in step-I was dissolved in 1320 ml of methanol and transferred into hydrogenator vessel containing 8.8 gms of Raney-nickel. The resultant reaction suspension was agitated under 6 kg/cm 2 to 8 kg/cm 2 hydrogen gas pressure at about 45°C for about 8 hours. The reaction progress was monitored by TLC (thin layer chromatography). After completion of reaction, reaction mass was cooled to about 30°C, the reaction suspension was filtered on celite bed to separate the catalyst and washed with methanol. The filtrates were combined and concentrated under reduced pressure to give crude product as liquid. The resulting crude product was suspended in 260 ml of ethyl acetate and stirred for about 1 hour at about 30°C. The solid separated was filtered and the solid obtained was washed with ethyl acetate followed by drying the solid to yield 72 gms of (R)-l-phenyl-2-[[2-(4-aminphenyl)ethyl] amino] ethanol monohydrochloride of formula (10 ) as crystalline solid.

SOR: [a]²⁵: -38.7° (c=0.5 in MeOH);

FTIR(KBr):3357, 3391, 2956, 1612, 1519, 1449, 1406, 1272, 1098, 1052, 924, 821, 756, 699 cm^"1 ^XH-NMR (400 MHz, DMSO-d₆): δ (ppm) = 2.84-2.86 (m, 2H), 2.98-3.13 (m, 4H), 5.03 (d, 3H), 6.22 (s, 1H), 6.51 (d, J=7.5 Hz, 2H), 6.86 (d, J=7.5 Hz, 2H), 7.28-7.37 (m, 5H), 9.3 (br s, 2H).

¹³C-NMR (400 MHz, DMSO-d₆): δ (ppm)= 30.9, 48.9, 53.9, 68.5, 114.5, 124.4, 126.2, 128.0, 128.6, 129.3, 142.2, 147.5.

MS: m/z=257 (M+H)⁺.

Method-(b): To a suspension of 10.0 gm (0.179 mol) of Iron (Fe) in 85 ml of water and

5.8 gms (0.052 mol) of hydrochloric acid, 17.0 gm (0.052 mol) of (R)-l-Phenyl-2-[[2-(4- nitro-phenyl)ethyl] amino] -ethanol hydrochloride of formula (2) obtained in step-I in methanol (50.0 ml) was added at about 80°C under stirring. The resultant reaction mixture was stirred at about 80°C for about 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was cooled to about 30°C, the reaction suspension filtered on celite bed to separate the catalyst iron and the celite was washed with methanol. The filtrates were combined filtrate and concentrated under reduced pressure to give crude product as liquid. The resulting crude product was purified in a mixture of ethyl acetate and methanol to get 12.8 gms of pure (R)-l-Phenyl-2-[[2-(4-aminphenyl)ethyl]- amino] ethanol monohydrochloride of formula (10) as crystalline solid. Step (III): Preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2- phenylethyl]amino]-ethyl)phenyl]acetamide (Mirabegron) of formula (1)

(10) (6) (1)

To the suspension of (25.0 gm, 0.085 mol) of (R)-l-Phenyl-2-[[2-(4- aminphenyl)ethyl]amino]ethanol monohydrochloride of formula (10) obtained in step-II in a mixture of 250 ml of acetonitrile and 125 ml of water, 15.0 gm, (0.094 mol) of 2- aminothiazol-4-acetic acid of formula (6) was added under stirring at about 30°C. The resultant reaction mixture was further stirred for about 10 mins. followed by addition of 11.4 gm, (0.10 mol.) of hydrochloric acid and portion wise addition of 26.2 gm (0.136 mol) of 1- (3-dimethylamino-propyl)-3-ethylcarbodiimide mono hydrochloride over about 15 min. The resultant reaction mixture was stirred at about 30°C for about 5 hours. The reaction progress was monitored by TLC (thin layer chromatography). After completion of the reaction, 40ml of 30% w/v sodium hydroxide solution was added to get basic pH. The organic and aqueous layers were separated and the organic layer was further cooled to about 5°C and stirred for about 12 hours. The solid separated was filtered and the solid was washed with 25 ml of precooled acetonitrile. The solid obtained was dried to obtain 18.8 gms of pure of 2- (2- aminothiazol-4-yl)-N- [4-(2- [ [(2R)-2-hydroxy-2-phenylethyl] amino] ethyl)-phenyl] acetamide (Mirabegron) of formula (1) as a -crystal form.

Purity by Chiral purity: 99.99 area %;

Differential scanning calorometry (DSC): 140.9-142.6°C. FTIR (KBr): 3390, 3352, 1654, 1598, 1522, 1445, 1426, 1411, 1338, 1117, 977, 900, 808, 699 cm^"1 ;

1H-NMR (400 MHz, DMSO-d₆): δ (ppm) = 1.63 (s, 1H), 2.48-2.67 (m, 5H), 2.70-2.78 (m, 2H), 3.44 (s, 2H), 4.57 (br s, 1H), 5.25 (br s, 1H), 6.29 (s, 1H), 6.91 (s, 2H), 7.09 (d, J=8.1 Hz, 2H), 7.15-7.19 (m, 1H), 7.21-7.31 (m, 4H), 7.48 (d, J=8.1 Hz, 2H), 10.0 (br s, 1H).

1³C-NMR (400 MHz, DMSO-d₆): δ (ppm) = 35.7, 51.1, 57.8, 71.7, 102.9, 119.3, 126.1, 126.2, 127.0, 128.2, 129.1, 135.4, 137.5, 144.9, 146.2, 146.2,168.1, 168.5.MS: m/z=397 (M+H)⁺.

Claims

We Claim:

1) An improved process for the preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2- hydroxy-2-phenylethyl] amino] -ethyl)phenyl]acetamide of formula (1)

(1)

comprising the steps of :

a) reacting the compound -(-)-l-phenyl-l,2-ethanediol 2-tosylate of formula (12),

(12 )

a compound 4-nitrophenylethylamine of formula (13 ),

(13)

in the presence of suitable organic solvent to afford (R)-l-Phenyl-2-[[2- (4- nitrophenyl)ethyl] amino] ethanol hydrochloride of formula (2)

(2)

b) subjecting the compound of formula (2) to catalytic hydrogenation in the presence of suitable catalyst and solvent to afford (R)-l-Phenyl-2-[[2-(4- aminphenyl)ethyl] amino] ethanol monohydrochloride of formula (10)

(10) c) reacting the compound of formula (10 ) with 2-aminothiazol-4-acetic acid of formula (6)

in the presence of suitable catalyst and a solvent to obtain pure compound 2-(2- aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl)phenyl]- acetamide of formula (1).

The process of claim 1 , wherein the suitable organic solvent used in step (a) is selected from group consisting of tetrahydrofuran (THF), 2-methyl THF, methyltertiarybutylether (MTBE), acetonitrile, 2-propanol, toluene or mixture thereof, preferably tetrahydrofuran (THF).

The process of claim 1, wherein the reaction step (a) is carried out at temperature from about 0°C to about reflux temperature of the solvent(s) used, preferably about 60°C and the time period is from about 10 to 20 hours, preferably for a period of 15 to 20 hours.

The process of claim 1, wherein the catalyst employed in step (b) is selected from the group consisting of raney nickel, palladium on carbon, palladium hydroxide, iron powder, zinc dust and stannous chloride or a mixture thereof in combination with metal, preferably palladium on carbon, raney nickel and iron powder, more preferably raney nickel.

The process of claim 1, wherein the solvent used in step (b) is selected from group consisting of methanol, ethanol, ethyl acetate, 2-propanol, water or mixture thereof, preferably methanol and ethyl acetate, more preferably methanol. 6) The process of claim 1 , wherein the reaction step (b) is carried out at a temperature from about 25°C to about 60°C, preferably from about 40°C to about 45°C and wherein the reaction time is from about 6 hours to about 10 hours, preferably of about 8 hours.

7) The process of claim 1 , wherein the suitable catalyst for coupling in the reaction step-(c) is selected from the group consisting of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide mono hydrochloride, Ν,Ν'-dicyclohexylcarbodiimide, hydroxybenzotriazole (HOBt), 2- (lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3- oxidohexafluorophosphate (HATU), benzotriazol- 1 -yl-oxytripyrrolidino-phosphonium hexafluorophosphate (PyBOP), benzotriazol- 1 -yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP), or mixture thereof; preferably the coupling agent l-(3- dimethylaminopropyl)-3-ethylcarbodiimide mono hydrochloride is being used.

8) The process of claim 1 , wherein the solvent used in reaction step (c) is selected from the group consisting of acetonitrile, tetrahydrofuran (THF), dichloromethane (DCM), 2- methyl THF, methyl tertiary butyl ether (MTBE), 2-propanol, toluene, and water or mixture thereof; preferably a mixture of acetonitrile and water in any proportion without limitation.

9) The process of claim 1 , wherein the reaction is carried out at a temperature from about 5°C to about 30°C; preferably from about 20°C to about 30°C and the reaction time is from about 2 hours to about 8 hours; preferably from about 4 to 5 hours.

10) The process of claim 1, wherein the step (c) reaction is optionally carried out in the presence of an acid wherein the acid can be inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trichloroacetic acid, trifluoroacetic acid or mixture thereof, preferably the acid used is hydrochloric acid.

11) A process for the preparation of (R)-l-Phenyl-2-[[2-(4-nitrophenyl)ethyl] amino] ethanol hydrochloride of formula 2

comprising:

reacting the compound (R -(-)-l -phenyl- 1,2-ethanediol 2-tosylate of formula (12),

(12 ) with a compound 4-nitrophenylethylamine of formula (13 ),

(13)

in the presence of suitable organic solvent to afford the compound (R)-l-Phenyl-2-[[2- (4-nitrophenyl)ethyl]amino]ethanol hydrochloride of formula (2).

12) A process for the preparation of compound (R)-l-phenyl-2-[[2-(4- aminophenyl)ethyl]amino]ethanol monohydrochloride of formula 10

(10)

comprising: subjecting the compound (R)-l-phenyl-2-[[2-(4-nitrophenyl)ethyl] amino] ethanol hydrochloride of formula (2)

(2)

to catalytic reduction or hydrogenation in the presence of suitable catalyst and solvent to afford the compound (R)-l-Phenyl-2-[[2-(4-aminphenyl)ethylamino] ethanol monohydrochloride of formula (10).

13) A process for the preparation of pure compound 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)- 2-hydroxy-2-phenylethyl] amino] -ethyl )phenyl]acetamide of formula (1)

(1)

comprising:

reacting the compound (R)-l-Phenyl-2-[[2-(4-aminphenyl)ethyl]amino]ethanol monohydrochloride of formula (10 )

(10) with a compound 2-aminothiazol-4-acetic acid of formula (6)

in the presence of suitable catalyst and a solvent to yield pure compound 2-(2- aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl)- phenyl]acetamide of formula (1).

14) The use of compound (R)-l-Phenyl-2-[[2-(4-nitrophenyl)ethyl] amino] ethanol

hydrochloride of formula (2)

(2) in the synthesis of 2-(2- aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2- phenylethyl]amino]ethyl)phenyl]acetamide of formula (1) and its analogous compounds.

15) The compound 2-(2-aminothiazol-4-yl)-N-[4-(2-[[(2R)-2-hydroxy-2- phenylethyl] amino] ethyl)phenyl]acetamide of formula (1) obtained by the process of claim 1 has following impurities

Impurity-A Impurity-B Impurity-C

Impurity- A 1 Impurity-B 1

less than about 0.1% by weight as determined by chiral HPLC.

16) 2-(2- aminothiazol-4-yl)-N- [4-(2- [ [(2R)-2-hydroxy-2-phenylethyl] amino] ethyl)- phenyl]acetamide of formula (1) having the optical purity greater than about 99.8 area % by chiral HPLC, chemical purity greater than about 99.8 area %, total impurities less than about 0.5 area % and single maximum impurity less than about 0.1 area % by HPLC.