WO2007086074A2

WO2007086074A2 - A process for the preparation of r (-) tamsulosin hydrochloride

Info

Publication number: WO2007086074A2
Application number: PCT/IN2006/000027
Authority: WO
Inventors: Venkatasubramanian Radhakrishnan Tarur; Nandu Baban Bhise; Dhananjay Govind Sathe; Anil Purushottam Joshi; Rajasundran Mannabeth Amrutaraj
Original assignee: Usv Limited
Priority date: 2006-01-27
Filing date: 2006-01-27
Publication date: 2007-08-02
Also published as: WO2007086074A3

Abstract

The invention discloses a process for the preparation of highly pure R (-)-5-(2-(2-(2-ethoxy phenoxy) ethylamine) propyl)-2-methoxy benzene sulfonamide hydrochloride used to treat symptoms of urinary difficulty. R-(-)-2-(4-methoxy phenyl)- 1 -methyl ethyl amine is condensed with halo-acetyl halide in the presence of base and a halogenated solvent. The resulting R-(-)- halo-N-[2-(4-methoxy phenyl)- 1 -methyl ethyl] acetamide is treated with chlorosulphonic acid and ammonia. R-(-)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)- 1 -methyl ethyl]-2- haloacetamide obtained is treated with 2- ethoxy phenol in the presence of an inorganic base and water to obtain R-(-)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)- 1 -methyl ethyl]-2-(2- ethoxy phenoxy) acetamide in high yield and purity. The amide obtained is reduced to obtain the Tamsulosin base, which is then purified and converted to its hydrochloride salt.

Description

A process for the preparation of R (-) Tamsulosin Hydrochloride

TECHNICAL FIELD:

The invention relates to a process for the preparation of R (-) Tamsulosin hydrochloride of the formula (I):

The chemical name of Tamsulosin is R (-)-5-(2-(2-(2-ethoxy phenoxy) ethylamine) propyl)-2- methoxy benzene sulfonamide. Tamsulosin and its salts are used to treat symptoms of urinary difficulty that occur with benign prostatic hyperplasia (BPH) i.e. a non-cancerous enlargement of the prostrate gland. Tamsulosin exhibits an action of blocking a specific (alpha) receptor and relaxes muscle tissue in the prostate and thus opens the bladder.

BACKGROUND OF THE INVENTION

WO02068382 describes a process for the preparation of R (-) Tamsulosin hydrochloride (I) by reacting R-(-)-5-[(2-amino-2-methyl) ethyl] -2-methoxy benzene sulfonamide of the formula (JI) with (2-ethoxy phenoxy)acetyl chloride of the formula (JH) in the presence of trialkyl amine or inorganic base and a solvent such as dimethylformamide, dimethylsulfoxide, dimethylacetamide or tetrahydrofuran to obtain 2-(2-ethoxy phenoxy)-N-[2-(4-methoxy-3- sulfamoyl-phenyl)-l-methylethyl]acetamide of the formula (IV). The compound (IV) is reduced with lithium aluminum hydride, borane, diisobutylaluminum hydride, sodium borohydride-iodine or sodium borohydride-sulfate to give R (-) Tamsulosin base (I a), which was further converted into its hydrochloride salt, R (-) Tamsulosin hydrochloride (T) as shown in the following reaction scheme 1 : Scheme 1

⁽TV)

Reduction

OEt

(I a)

The yield of the reaction depends on the purity of (2-ethoxy phenoxy)acetic acid or (2-ethoxy phenoxy)actyl chloride. It is known in the art that purification of such products is not easy thereby affecting the overall yield. Further it is difficult to use lithium hydride as reducing agent on an industrial scale because of its pyrophoric properties and tedious work up.

JP H2-295967 and 2-306958 describe the process for the preparation of R (-) Tamsulosin hydrochloride (T) by condensing R (-)-2-(4-methoxy phenyl)- 1 -methyl ethyl amine of the formula (VT) with bromoacetic acid and trimethyl acetyl chloride in the presence of triethylamine in chloroform to give R (+)-bromo-N-[2-(4-methoxy phenyl)- 1 -methyl ethyl ]acetamide of the formula (VTT). The compound (VD) is then reacted with chlorosulphonic acid and ammonia in chloroform to give R(+)-N-[2-(3 -amino sulfonyl-4-methoxy phenyl)- 1 -methyl ethyl ]-2-bromo acetamide of the formula (VTTT) followed by treatment with 2-ethoxyphenol in the presence of potassium carbonate in N,N-dimethyl sulfamide to give R (-)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)- 1 -methyl ethyl ]-2-(2-ethoxy phenoxy) acetamide of the formula (IV). The compound (IV) is further reduced by a reducing agent such as diborane or lithium aluminum hydride in tetrahydrofuran to obtain the Tamsulosin base (I a) as shown in the reaction scheme 2:

Scheme 2

ClSO₃H₁ NH₃ g3S, CHC^

(IV)

(VIII)

Reduction

On carrying out the process as described above, it was found to be lengthy and giving low yield (about 25 %). The use of combination of bromoacetic acid and trimethyl acetyl chloride for the preparation of compound (VH) leads to a two step reaction involving formation of mixed anhydride or acid chloride followed by amidation resulting in lengthy procedure. The patent does not disclose the purity of Tamsulosin hydrochloride.

US 4731478 discloses a process for the preparation of R (-) Tamsulosin hydrochloride (1) by condensing R -(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxy benzene sulfonamide of the formula (H) with (2-ethoxy phenoxy)ethyl bromide (V) in ethanol yielding oily Tamsulosin base which is further extracted in ethyl acetate followed by distillation of the solvent to obtain a residue comprising Tamsulosin base (Ia). The residue is purified by silica gel column chromatography using eluent system such as chloroform and methanol (9:5) to provide crystal of Tamsulosin base which is further converted to its hydrochloride salt. The Compound II is prepared by acylating compound (Vl) with acetic anhydride and pyridine, followed by treatment with chlorosulphonic acid and subsequently with ammonia and finally hydrolysis. The reaction is shown in the reaction scheme 3:

Scheme 3

H₃CO

m

OEt

(I a)

The compound (II) is used as a free base in the process and condensed with the compound (V) to obtain Tamsulosin base, which is found to be contaminated with unreacted compound (II). Therefore the Tamsulosin base is required to be purified to remove unreacted compound H The compound (It) is expensive and hence needs to be consumed in the reaction completely to give an economical process or needs to be recovered and recycled in the process.

WO2005056521 describes the process for the preparation of optically pure R (-) Tamsulosin hydrochloride (I) by treating R-2-(4-methoxy-3-aminosulfonyl-phenyl)-l -methyl ethyl amine (VI) with a haloacetic acid, a haloacetic anhydride or haloacetyl halide in the presence of a base such as trialkyl amine or inorganic base and an inert solvent such as dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, tetrahydrofuran or methylene chloride to give R-2- halo-N-[2-(4-methoxy-3-aminosulfonyl phenyl)- 1 -methyl ethyl] acetamide (VIH) followed by treating it with 2-ethoxy phenol in the presence of base in organic solvent to give R-2-(2- ethoxy phenoxy)-N-[2-(4-methoxy-3-aminosulfonyl-phenyl)-l -methyl ethyl] acetamide (IV). Then the compound (IV) is reduced using sodium borohydride -boron triflouride etherate complex or lithium aluminum hydride to obtain Tamsulosin base (I a) as shown in the reaction scheme 4:

Scheme 4

2- ctliorjφhcnol

(I a) (N)

The final compound is purified by crystallization or chromatography. The above process uses combination of haloacetic acid and its anhydride or haloacetyl halide thereby rendering it lengthy. The purity of Tamsulosin hydrochloride obtained is not reported.

WO2005051897 discloses preparation of Tamsulosin, involving a coupling reaction of methyl 2-ethoxy phenoxy acetate and R-5-(2-amino)propyl-2-methoxy benzene sulfonamide (IT) in the presence of aluminum reagent and a aprotic solvent to obtain Tamsulosin amide, which is reduced with sodium bis(2-methoxy ethoxy) aluminum dihydride or borane dimethyl sulfide to obtain Tamsulosin base (I a). The aluminum reagent used in this process is trivalent aluminum reagent like disiobutylaluminum hydride, trimethyl aluminum, triethyl aluminum, dimethyl aluminum chloride, aluminum isopropoxide, aluminum trichloride. The reaction is as shown in the reaction scheme 5: Scheme 5

Aluminium reagent, aprotic solvent

(W)

Reduction

OEt

(I a)

Use of aluminum reagent for the formation of Tamsulosin amide (IV) is difficult at industrial scale. The patent does not disclose the purity of the Tamsulosin hydrochloride or any of its intermediates.

OBJECTS OF THE INVENTION

An object of the invention is to provide a process for the preparation of R (-) Tamsulosin hydrochloride in high yield and high purity.

Another object of the invention is to provide a process for the preparation of R (-) Tamsulosin hydrochloride, which is simple, easy and convenient to carry out, cost-effective and efficient.

Another object of the invention is to provide a process for the preparation of R (-) Tamsulosin hydrochloride, which reduces waste generation and disposal problems and is eco-friendly.

Another object of the invention is to provide a process for the preparation of an intermediate of. R (-) Tamsulosin hydrochloride, 2-(2-ethoxy phenoxy)-N-[2-(4-methoxy-3-sulfamoyl-phenyl)- 1 -methyl ethyl] acetamide (IV), which is simple, easy and convenient to carry out, cost- effective and efficient.

Another object of the invention is to provide a process for the preparation of an intermediate of R (-) Tamsulosin hydrochloride, 2-(2-ethoxy phenoxy)-N-[2-(4-methoxy-3-sulfamoyl-phenyl)- 1 -methyl ethyl] acetamide (IV), which reduces waste generation and disposal problems and is eco-friendly.

DETAILED DESCRIPTION

According to the invention there is provided a process for the preparation of R (-) Tamsulosin hydrochloride of the formula (I):

the process comprising of

(i) reacting a compound of the formula (VI) :

(VD

Formula (VI) with a haloacetyl halide¹ selected from bromoacetyl bromide, bromoacetyl chloride, chloroacetyl chloride or chloroacetyl bromide in a 1: 1.2-1.3 mole ratio in the presence of base selected from pyridine, triethyl amine, N- methyl morpholine or Hunig's base in a halogenated solvent selected from dichloro methane or chloroform at a temperature in the range of 0 to 5° C to obtain a compound of the formula (DC);

Formula (IX) wherein [X = Cl, Br, I]

(ϋ) treating the compound of the formula (IX) with chlorosulfonic acid at -5 to - 10° C followed by treatment with ammonia such as ammonia gas, liquor ammonia or ammonium carbonate at 10 to 20° C to obtain a compound of the formula (VH);

Formula (VII)

(iϋ) condensing the compound of the formula (VIT) with 2-ethoxy phenol in the presence of inorganic base selected from sodium hydroxide, potassium hydroxide or lithium hydroxide and water to obtain a compound of the formula (IV);

(iv) reducing the compound of the formula (IV) with borane complex selected from diborane, borane-tetrahydrofuran or borane-dimethylsulfide to obtain Tamsulosin base of the formula (I a);

Formula (I a) (V) purifying the Tamsulosin base (I a) by column chromatography using a silica gel as a stationary phase and a mobile phase selected from a mixture of halogenated solvent such as dichloromethane or chloroform and alcohol such as methanol, ethanol or isoproanol; and

(Vi) converting the Tamsulosin base (I a) into its hydrochloride salt followed by recrystallizing it with ethyl alcohol and water to obtain crystals of R (-) Tamsulosin hydrochloride (I).

According to the invention there is also provided a process for the preparation of an intermediate of R (-) Tamsulosin hydrochloride, 2-(2-ethoxy phenoxy)-N-[2-(4-methoxy-3- amino sulfonyl-phenyl)-! -methyl ethyl] acetamide (IV):

Formula (IV) the process comprising of

(i) reacting a compound of the formula (VI):

Formula (VI) with a haloacetyl halide selected from bromoacetyl bromide, bromoacetyl chloride, chloroacetyl chloride or chloroacetyl bromide in a 1: 1.2-1.3 mole ratio in the presence of base selected from pyridine, triethyl amine, N- methyl morpholine or Hunig's base in a halogenated solvent selected from dichloro methane or chloroform at a temperature in the range of O to 5° C to obtain a compound of the formula (IX);

Formula (IX) wherein [X = Cl, Br, I] (ii) treating the compound of the formula (IX) with chlorosulfonic acid at -5 to - 10° C followed by treatment with ammonia such as ammonia gas, liquor ammonia or ammonium carbonate at 10 to 20° C to obtain a compound of the formula (VII); and

Formula (VIT) (iii) condensing the compound of the formula (VII) with 2-ethoxy phenol in the presence of inorganic base selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide and water to obtain a compound of the formula (IV).

The haloacetyl halide used in step (i) is preferably chloroacetyl chloride. The base used in step (i) is preferably triethyl amine. The halogenated solvent used' in step (i) is preferably chloroform. The ammonia used in step (ii) is preferably liquor ammonia. The inorganic base used in step (iii) is preferably sodium hydroxide. Instead of water, the solvent used in step (iii) can be tetrahydrofuran or dioxan or their mixtures. The borane complex used in step (iv) is preferably borane-dimethlsulfoxide (BMS). The mobile phase used in step (v) is preferably mixture of dichloromethane and methanol.

According to the invention the yield of the intermediate of R (-) Tamsulosin hydrochloride, 2- (2-ethoxy phenoxy)-N-[2-(4-methoxy-3-sulfamoyl-phenyl)-l -methyl ethyl] acetamide (TV), obtained by the above process is 73 % with 92 % purity. The yield of R (-) Tamsulosin hydrochloride (I) obtained by the above process is 87 % with 99.8 % purity. Only a single reagent, halo acetyl halide is used in step (i) instead of combinations of halo acetic acid, acetic anhydride and halo acetyl halide reagents used in the prior art. All the reactions are carried out in water and the reagents used can be easily handled at industrial scale unlike aluminium hydride. Therefore, the above process is simple, easy and convenient to carry out. The product as well as its intermediates are obtained in good yield and purity without the necessity of extensive purification of the intermediates. Therefore, the process is cost-effective. It avoids the use of organic solvent or requires minimum quantity of organic solvent for work up which can be recovered and recycled. Thus there is no wastage of solvent and no waste disposal problem and the process is eco-friendly.

The following experimental example is illustrative of the invention but not limitative of the scope thereof:

Example

(i) R (-)-chloro-N-[2-(4-methoxy phenyl)-l -methyl ethyl] acetamide (IX)

A solution of R(-)-2-(4-methoxy phenyl)- 1 -methyl ethyl amine(100 g, 0.60 mole), triethyl amine (91 g, 0.90 mole) in chloroform (600ml) was stirred at 0-5⁰C and chloroacetyl chloride (86.0 g, 0.76 mole) was added in a dropwise manner for 2 h. The reaction mixture was stirred at room temp for 20-24 h. The reaction mixture was washed with dilute hydrochloric acid, aqueous sodium carbonate solution and water. The organic layer was separated and concentrated under vaccum. The residue obtained was precipitated from 1000 ml of hexane. The solid formed was filtered, washed with hexane and dried. Yield: 138.0 g (95%) , HPLC: 95%. •

(ii) R-(-)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)-l -methyl ethyl] -2-chloroacetamide (VII)

R-(-)-chloro-N-[2-(4-methoxy phenyl)- 1 -methyl ethyl] acetamide (DC) (80 g, 0.33 mole) was added in parts into a flask containing chlorosulphonic acid (385 g, 3.31 mole) at -5 to -10° C over a period of 2 hour. On complete addition the reaction mixture was stirred for 2 hour at room temperature. The reaction mixture was poured into ice-water. The solid was separated, filtered and washed with cold water. The solid was dissolved in tetrahydrofuran (500 ml) and Liquor ammonia solution (150 ml) was added dropwise manner into it at 10 to 15°C for 1 hour. On the complete addition the reaction mixture was stirred for 2 hour at 15-20° C. The solid obtained was filtered and dried. Yield: 85 g (80%), HPLC: 95% (iii) R-(~)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)-l -methyl ethyI]-2~(2-ethoxy phenoxy) acetaniide (TV)

A solution of 2-ethoxy phenol (431 g, 3.12 mole) in 3-5% aqueous sodium hydroxide solution (3500 niL) was heated at 65-70° C for 15 min. Then R-(-)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)- 1 -methyl ethyl] -2-chloroacetamide (X) (125 g, 0.39 mole) was added to the reaction mixture in parts for 1 hour at 65-70° C. The reaction mixture was acidified with concentrated hydrochloric acid and extracted with 2000 ml of chloroform. The chloroform was separated, washed with dilute sodium hydroxide solution, brine and concentrated to obtain a residue. The residue was treated with 2000 ml of hexane to obtained a solid, filtered and dried. Yield: 120 g (73%), HPLC: 92%.

(iv) R (-)-5-(2-(2-(2-ethoxy phenoxy) ethylamine) propyl)-2-methoxy benzene sulfonamide (Tamsulosin base)(I a)

R-(-)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)- 1 -methyl ethyl] -2-(2-ethoxy phenoxy) acetamide (IV) (120 g, 0.303 mole) was suspended in tetrahydrofuran (1200 ml) and stirred at 15° C. Borane-dimethyl sulfide (224 g, 2.84 mole) was added to it in a dropwise manner for 1 hour at 15° C. The reaction mixture was stirred for 6-8 hour at 15°C followed by addition of methanol (400 ml) and concentrated hydrochloric acid (90 ml) to the reaction mixture. The reaction mixture was refluxed for 2 hour and concentrated to obtain the residue. The residue obtained was taken in acetone (720 ml) and water (2400 ml) was added. This solution was basified with sodium carbonate solution and solid obtained was filtered. Yield: 90.0 g (75%), HPLC: 95-96%

(v) Purification of Tamsulosin base (I a)

Crude Tamsulosin base (T) (90 g) was dissolved in dichloromethane and adsorbed on silica gel. This adsorbed material was loaded on small silica gel layer and eluted with 2% methanol in dichloromethane. The pure Tamsulosin base was obtained. Yield: 82.0 g (91%), HPLC: >99%. (vi) Tamsulosin hydrochloride (I)

The pure Tamsulosin base (80 g) was dissolved in ethyl alcohol (320 ml) and alcoholic HCl was added at room temperature. The mixture was stirred for 2 hour. The solid was separated and filtered. The collected solid was recrystallised from ethyl alcohol- water (4: 1). Yield: 80.0 g (87%), HPLC: >99.8%.

Claims

CLAIMS:

1. A process for the preparation of R (-) Tamsulosin hydrochloride of the formula (I):

the process comprising of

(i) reacting a compound of the formula (VI):

Formula (VI) with a haloacetyl halide selected from bromoacetyl bromide, bromoacetyl chloride, chloroacetyl chloride or chloroacetyl bromide in a 1: 1.2-1.3 mole ratio in the presence of base selected from pyridine, triethyl amine, N- methyl morpholine or Hunig's base in a halogenated solvent selected from dichloro methane or chloroform at a temperature in the range of 0 to 5° C to obtain a compound of the formula (IX);

Formula (IX) wherein [X = Cl, Br, I] (ii) treating the compound of the formula (IX) with chlorosulfonic acid at -5 to -

10° C followed by treatment with ammonia such as ammonia gas, liquor ammonia or ammonium carbonate at 10 to 20° C to obtain a compound of the formula (VIT);

(iii) condensing the compound of the formula (VII) with 2-ethoxy phenol in the presence of inorganic base selected from sodium hydroxide, potassium hydroxide or lithium hydroxide and water to obtain a compound of the formula (IV);

Formula (IV) (iv) reducing the compound of the formula (IV) with borane complex selected from diborane, borane-tetrahydrofuran or borane-dimethylsulfide to obtain Tamsulosin base of the formula (I a);

Formula (I a)

(v) purifying the Tamsulosin base (I a) by column chromatography using a silica gel as stationary phase and a mobile phase selected from a mixture of halogenated solvent such as dichloromethane, or chloroform and alcohol such as methanol, ethanol or isoproanol; and

(vi) converting the Tamsulosin base (I a) into its hydrochloride salt followed by recrystallizing it with ethyl alcohol and water to obtain crystals of R (-) Tamsulosin hydrochloride (T).

2. The process as claimed in claim 1, wherein the haloacetyl halide used in step (i) is chloroacetyl chloride.

3. The process as claimed in claim 1, wherein the base used in step (i) is triethyl amine.

4. The process as claimed in claim 1, wherein the halogenated solvent used in step (i) is chloroform.

5. The process as claimed in claim 1, wherein the ammonia used in step (ii) is liquor ammonia.

6. The process as claimed in claim 1, wherein the inorganic base as per step (iii) is sodium hydroxide.

7. The process as claimed in claim 1, wherein the borane complex used in step (iv) is borane-dimethylsulfide.

8. The process as claimed in claim 1, wherein the mobile phase used in step (v) is mixture of dichloromethane and methanol.

9. A process for the preparation of an intermediate of R (-) Tamsulosin hydrochloride, 2- (2-ethoxy phenoxy)-N-[2-(4-methoxy-3-sulfamoyl-phenyl)-l-methyl ethyl] acetamide (IV):

the process comprising of

(i) reacting a compound of the formula (VI):

Formula (VI) with a haloacetyl halide selected from bromoacetyl bromide, bromoacetyl chloride, chloroacetyl chloride or chloroacetyl bromide in a 1: 1.2-1.3 mole ratio in the presence of base selected from pyridine, triethyl amine, N- methyl morpholine or Hunig's base in a halogenated solvent selected from dichloro methane or chloroform at a temperature in the range of 0 to 5° C to obtain a compound of the formula (DC);

10° C followed by treatment with ammonia such as ammonia gas, liquor ammonia or ammonium carbonate at 10 to 20° C to obtain a compound of the formula (VII); and

Formula (VII)

(iii) condensing the compound of the formula (VII) with 2-ethoxy phenol in the presence of inorganic base selected from sodium hydroxide, potassium hydroxide or lithium hydroxide and water to obtain a compound of the formula (IV).

10. The process as claimed in claim 9, wherein the haloacetyl halide used in step (i) is chloroacetyl chloride.

11. The process as claimed in claim 9, wherein the base used in step (i) is triethyl amine.

12. The process as claimed in claim 9, wherein the halogenated solvent used in step (i) is chloroform.

13. The process as claimed in claim 9, wherein the ammonia used in step (ii) is liquor ammonia.

14. The process as claimed in claim 9, wherein the inorganic base as per step (iii) is sodium hydroxide.