Title of the Invention
An improved process for the preparation of Tauroursodeoxy cholic acid.
Field of the Invention
The present invention related to an improved process for the preparation of
Tauroursodeoxycholic acid having the chemical structural Formula I.
Background of the Invention
Tauroursodeoxycholic acid, chemical name is N-(3-alpha,7-beta-dihydroxy-5-beta-cholan-24-oyl)-taurine, has the effects such as antispasmodic, anticonvulsant, antiinflammatory and dissolving cholelithiasis. Tauroursodeoxycholic acid mainly exists in black bear bile and is the iconic active ingredient in bear bile. In 2007, Tauroursodeoxycholic acid capsules with the trade name of Taurot were approved for sale in China. It is mainly used for dissolving cholesterol stories.
The drug and its preparations have been marketed in foreign countries for 20 years and are mainly used for steroid gallstones, cholestatic liver diseases (such as primary biliary cirrhosis), bile reflux gastritis, Autoimmune hepatitis (AlH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), chronic hepatitis (hepatitis B, hepatitis C, etc.), alcoholic fatty liver, non-alcoholic fatty liver, Drug-induced liver damage, prevention and treatment of complications before and after liver transplantation, etc. The drug was first registered and marketed in 1992 by Bruschettini S.RL, Italy's Besti
Pharmaceuticals. The chemical structure of Tauroursodeoxycholic acid is shown below.
Italian patent IT1197330 describes the preparation of a mixed anhydride of tauroursodeoxycholic acid by reaction between ursodeoxycholic acid and an alkyl chloroformate in the presence of a tertiary base, which is reacted with an alkaline aqueous solution of taurine to obtain the sodium salt of tauroursodeoxycholic acid. Subsequent addition of hydrochloric acid and removal of the solvents by vacuum concentration make it possible to obtain a residue containing tauroursodeoxycholic acid. Resuspending the residue with ethanol and subsequent filtration remove the unreacted taurine and sodium chloride, while the tauroursodeoxycholic acid remains in solution. The latter is then precipitated out from the solution by addition of a solvent in which said acid is insoluble. The product is finally dissolved in water and reprecipitated in the solvent in order to reduce the solvent content in the precipitate. The problem with this synthetic route is the low yield, and that it furthermore involves multiple steps which hinders putting it into practice on an industrial scale.
European patent application EP400695 describes the preparation of tauroursodeoxycholic acid by means of a purification process of the solution obtained by reaction between taurine and a mixed anhydride of ursodeoxycholic acid in the presence of a tertiary base. In order to avoid the addition of a mineral acid (such as hydrochloric acid) to the sodium salt of tauroursodeoxycholic acid, a procedure which éfit’ailS ‘vafi'dUs pU’r‘ifiCa‘tiOfi steps, the solution arising from the reactiOn between taurine and the mixed anhydride is passed in sefies through a first strong cationic exchange resin and through a second weak anionic exchange resin. The disadvantage is that the ion exchange column is more troublesome to pack and regenerate.
10 Chinese patent application CN102718829 descfibes the preparation of sodium tauroursodeoxycholate, which is schematically shown below
The problem with this synthetic route is the low yield, and that it furthermore involves 15 mulfiple steps of purification by column chromatography, which hinders putting it into practice on an industn’al scale.
Several processes for prepé‘raiti'o‘fi 'of Taur'oursodeoxycholic acid of Formula I and its intermediates have been disclosed in EP629634, EP272462, CN 102994604 and CN 20 107287272. Nevertheless, these synthetic routes are includes several steps of
purification by célumn chromatography, rendering its unsuitable for industrial implementation.
In View Of the ifflpéi‘tfifléé 5f t'féétiflg Enid fiféVefi'ting disOfdefS hSSébiitéd With blfiék bea: bile and is the iconic active ingredient in bear bile, it would be desirable and of paramount importance to have a process for the preparation of Tauroursodeoxycholic acid of Formula L by employing inexpensive, readily available, easy to handle reagents.
It would 21136 be déSiffiblé 10 have a pi‘bfzéSS 1t C5111 be 'f‘eiidily SCéléd up and Whiéh does not require a special purification step, thereby making it mofe suitable for industrial scale preparation.
Summary of the Invention
The present invention provides a cost effective, novel and an efficient process for the preparation of Tauroursodeoxycholic acid compound of Formula I with higher yields and better purity.
In one aspect, the present invention provides an improved process for the prepaxation of Tauroursodeoxycholic acid having the structural Formula I,
which comprises: i. condensation of alkali metal salt of Ursodeoxycholic acid
with ethyl chloroformate in presence of suitable solvent or mixture of organic solvents to obtained mixed anhydride of UDCA having the sttuctura] Formula II. ii. condensation of mixed anhydxide of UDCA having the structural Formula II
with taurine triethylamine salt (or)2-aminoethanesulphonic acid in presence of suitable acid(or) base and solvent or mixture of organic solvents to obtained Tauroursodeoxycholic acid having the compound of Formula 1.
Detailed Description of the Invention 15 Accordingly, the present invention provides an improved process for the preparation of Tauroursodeoxycholic acidhaving the compound of Formula I.
The main aspect of the present invention provides an improved process fpr the preparation of Tauroursodeoxycholic acid having the compound of Formula I, which 20 is outlined below in Scheme-II.
Step i) condensation of alkali metal salt of Ursodeoxycholic acid with ethyl chloroformate in presence of suitable solvent or mixture of organic solvents to obtained mixed anhydride of UDCA having the structural Formula II.
Step ii) condensation of mixed anhydn'de UDCA having the structural Formula II with 10 taurine tfiethylamine salt (or) 2-minoethanesulphonic acid in presence of suitable base(or) acid and solvent 01; mixture of organic solvents to obtained Tauroursodeoxycholic acid having the compound of Formula 1.
Solvent is selected from the group consisting of alcoholic solvent such as methanol, 15 ethanol, n-propanol, isopropanol, n-butanol, pentanol, isobutanol and the like; ester solvent such as ethyl acetate, butyl acetate and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon such as toluene, xylene and the like. Specifically, the solvent may be an aromatic hydrocarbon solvent and water or
mixtures.
Base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or organic bases includes but not limited to triethylamine, N—methyl pyrrolidone and like.The suitable acid may be selected from an organic acid such as oxalic acid, methane sulfonic acid and the like; and an inorganic acid such as hydrochloric acid, sulfuric acid and the like.
EXPERHVIENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Examplel: Process for the preparation of Tauroursodeoxycholic Acid (TUDCA) Step I: Process for the preparation of Sodium salt of Ursodeoxycholic Acid Ursodeoxycholic acid (100 grams) was taken in acetone (500 mL) at ambient temperature and stirred for 15 minutes. Then added sodium hydroxide solution
.
(Sodium Hydroxide (1018 grams) in Water (10.2 mL)) to the reaction mass over a time of 30 minutes at ambient temperature and maintained for 1 hour at same temperature.
Filtered the slurry mass and washed the solid with acetone (100 mL).Unloaded and dried the wet solid under vacuum at 60 °C for 6-8 hours to obtained Sodifim salt of Ursodeoxycholic Acid.
Yield: 95 grams; Purity: 99.5% (HPLC).
Step 11: Process for the preparation ofMixed Anhydride ofUrsodeoxycholic Acid.
Sodium salt of Ursodeoxycholic Acid (100 grams) was taken in acetone (600 mL) at ambient temperature. Then cooled the solution to 0 to 5 oC and added ethylchloroformate (28.79 grams) to the above reaction mass over the pen'od of 15 to
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20
25
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30 minutes. Stirred the resulting reaction mass for 30 minutes and filtered the sodium chloride salt by-product formed during the course of reactionand washed with acetone
(50 mL).
Filtrate contajning mixed anhydride of Ursodeoxycholic Acid (Formula 1]) is forwarded to next condensation reaction with taun'ne tn'ethylamine salt in step-III
without isolation.
Step 1]]: Process for the preparation of TaurineTriethyl amine salt solution.
Charged taurine (38.25 grams) in water (765 mL) at ambient temperature. Then cooled to 10-15 0C and added triethyl amine (3092 grams) to the reaction mass at 10-15 0C and stirred for 30 minutes toobtain Taurine triethyl amine salt.
Step IV: Process for the preparation of Tauroursodeoxycholic Acid (TUDCA).
Mixed anhydride of Ursodeoxycholic Acid (Step II) was added TaurineTn'ethyl amine salt solution (Step III) at ambient temperature then stirred for 30 minutes.Added Concentrated Hydrochloric acid (34.8 mL) to the above reaction and stirred for 1 hour at ambient temperature, Add acetone (920 mL) and maintained the reaction mass for I 2-15 hours resulted solid was separated, filtered and washed the wet solid with acetone (50 mL) to obtained crude Tauroursodeoxycholic acid.
Purified the crude Tauroursodeoxycholic acid in water (100 mL) at ambient temperature and obtained pure Tauroursodeoxycholic acid.
Yield: 126 grams (Crude) & 110 grams (Pure) Purity: ~ 90-93% HPLC (Crude) & 99.5% HPLC (Pure)
Example 2: Process for the preparation of Tauroursodeoxycholic Acid (TUDCA) Step I: Process for the preparation of Sodium salt of Ursodeoxycholic Acid Ursodeoxycholic acid (100 grams) was taken in acetone (500 mL) at ambient temperature and stirred for 15 minutes. Then added potassium hydroxide solution (Potassium Hydroxide (14.29 grams) in Water (102 mL)) to the reaction mass over a time of 30 minutes at ambient temperature and maintained for 1 hour at same temperature. Filtered the slurry mass and washed the solid with acetone (100 mL). Unloaded and dried the wet solid under vacuum at 60 °C for 6-8 hours to obtained Potassium salt of Ursodeoxycholic Acid.
Yield: 95 grams;Purity: 99.4% (HPLC)
Step H: Process for the preparation of Mixed Anhydride of Ursodeoxycholic Acid. Potassium salt of Ursodeoxycholic acid (100 grams) was taken in acetone (600 mL) at ambient temperature. Then cooled the solution to 0 to 5 °C and added ethyl chloroformate (27.71 grams) to the above reaction mass over the period of 15 to 30 minutes. Stirred for 30 minutes and filtered the formed potassium chloride salt and washed with acetone (50 mL). Unloaded Mixed anhydride of UDCA and forwarded this solution to Step —III in-situ without isolation.
Step JU: Process for the preparation of TaurineTriethyl amine salt solution.
Charged taurine (38.25 grams) in water (76.5 mL) at ambient temperature. Then cooled to 10-15 °C and added tri ethyl amine (30.92 grams) to the reaction mass at 10-15 °C and stirred for 30 minutes to obtained Taurine triethyl amine salt.
Step IV: Process for the preparation of Tauroursodeoxycholic Acid (TUDCA).
Mixed anhydride of Ursodeoxycholic Acid (Step II) was added TaurineTriethyl amine salt solution (Step HI) at ambient temperature then stirred for 30 minutes and added Concentrated Hydrochloric acid (36.5 mL) to the above reaction and stirred for 1 hour at ambient temperature. Add acetone (920 mL) and maintained for 12-15 hours solid was separated, filtered and washed the wet solid with acetone (50 mL) to obtained crude Tauroursodeoxycholic acid. Purified the crude Tauroursodeoxycholic acid in water (100 mL) at ambient temperature to obtained pure Tauroursodeoxycholic acid.
Yield: 122 grams (Crude) & 108.5 grams (Pure)
Purity: ~ 93.5% HPLC (Crude) & 99.4% HPLC (Pure)
Example 3: Process for the preparation of Tauroursodeoxycholic Acid (TUDCA).
Step 1: Process for the preparation of Mixed Anhydride of Ursodeoxycholic Acid.
Sodium salt of Ursodeoxycholic Acid (100 grams) was taken in acetone (600 mL) at ambient temperature Then cooled the solution to 0 to S 0C and added ethyl chloroformate (28,79 grams) to the above reaction mass over the period of 15 to 30 minutes. Stirred for 30 minutes and filtered the sodium chloride salt by-product formed during the course of reaction and washed with acetone (50 mL).
Filtrate containing Mixed Anhydride of Ursodeoxycholic Acid (Formula H)is forwarded to next condensation reaction with taurine triethylamine salt in step-III
without isolation.
Step 11: Process for the preparation of 'l‘aurineTriethyl amine salt solution.
Charged taurine (38.25 grams) in water containing sodium hydroxide (12.22 grams) at ambient temperature Then stirred for 30 minutes at 10-15 0C to obtained Taurine sodium amine szilt.
Step 1]]: Process for the preparation of Tauroursodeoxycholic Acid (TUDCA).
Mixed anhydride of Ursodeoxycholic Acid (Step I) was added Taurine sodium salt solution (Step II) at ambient temperature then stirred for 30 minutes and added Concentrated Hydrochloric acid (37 mL) to the above reacn'on and stirred for 1 hour at ambient temperature. Add acetone (920 mL) to above reaction and maintained for 12- 15 hours, solid was separated, filtered and washed the wet solid with acetone (50 mL) to obtained crude Tauroursodeoxycholic acid. Pun'fied the crude Tauroursodeoxycholic acid in water (100 mL) at ambient temperature to obtained pure Tauroursodeoxycholic acid.
Yield: 126.2 grams (Crude) & 111 grams (Pure) Purity: ~ 92.8 % HPLC (Crude) & 98.6 % HPLC (Pure)
Example 4: Process for the preparation of Tauroursodeoxycholic Acid (TUDCA).
Under nitrogen, Ursodeoxycholic acid methyl ester (10.0 grams) was taken Methanol (100 mL) and charged 2-aminoethanesulphonic acid (3.69 grams), catalytic amount of Triethylamine to the above reaction mass at ambient temperature. Then heat to reflux and maintained for 4-8 hours. Checked the unreacted UDCA Methyl ester by TLC or HPLC. Distilled out methanol and upon workup and isolation by aqueous Hydrochloric acid to obtained Tauroursodeoxycholic acid.
Yield: 12 grams; Purity: 98.50 % (HPLC)
The present invention has the following advantages:
• Our process is more economical due to higher % yield than disclosed processes in other patents.
• Process is more operation friendly in term of work up.
• Reduced time cycle
• Cost effective process.
• Avoided salt formation of Tauroursodeoxycholic acid for the purification purposes.
• No chromatographic purification adopted to achieve the desired quality.
• Preparation of Mixed anhydride of UDCA using Sodium/ Potassium salt by novel process.
We Claim:

1, An improved process for the preparation of Tauroursodeoxycholic acid (TUDCA) having the structural Formula 1
which composes:
i. condensation of alkali metal salt of Ursodeoxycholic acid with ethyl chloroformate in presence of suitable solvent or mixture of organic solvents to obtained mixed anhydn'de of UDCA having-the structural Formula I].
ii. condensation of mixed anhydride of UDCA having the structural Formula II with taurine triethylamine salt (or) 2-aminoethanesulphonic acid in presence of suitable solvent or mixture of organic solvents followed by acid (or) base to obtained Tauroursodeoxycholic acid (TUDCA) having the structural Formula I.
2. The process as claimed in claim 1, wherein said solvent is selected from the group consisting of alcoholic solvent ester solvent ketone solvent or aromatic hydrocarbon.
3. The process as claimed in claim 1, wherein said base is selected from group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, organic bases or acid.
4. The process as claimed in claim 3, wherein said acid is selected from organic acid or inorganic acid.