DESC:This application claims priority to Indian provisional patent application no. 201641032567 filed on September 23, 2016
Field of the invention:
The present invention relates to a process for preparing tiotropium bromide and more particularly, to an improved process for preparing tiotropium bromide and intermediates thereof.
Background of the invention:

Tiotropium bromide chemically described as (1a,2ß,4ß,7ß)-7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide, is an anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease. Tiotropium bromide is a very potent agent and therefore even very small amounts show therapeutic effect.

Many known processes of synthesis of tiotropium bromide involve the use of Datura seeds as a natural source for natural route of synthesis. The preparation of tiotropium bromide on commercial scale becomes difficult via natural route of synthesis. Further, for these processes quality seeds of Datura are rarely available which are hazardous to use.

Accordingly there is need of a synthetic, eco-friendly, non- hazardous and cost effective process for preparing tiotropium bromide and intermediates thereof that overcomes the above mentioned drawbacks of the prior art.

Summary of the invention:
Described herein is a process for synthesis of tiotropium bromide starting from optically pure dimethyl tartarate. Also described is synthesis of scopine starting from optically pure dimethyl tartarate.
In one aspect, provided herein is a process for the manufacture of tiotropium bromide of Formula 1 comprising

(i) protecting a compound of Formula 2 to obtain a compound of Formula 3

wherein Bn is a protecting group;

(ii) reducing the compound of Formula 3 to a compound of Formula 4
;

(iii) oxidizing the compound of Formula 4 to a compound of Formula 5
;

(iv) condensing the dialdehyde of Formula 5 with acetone-1,3-dicarboxylic acid and methyl amine to obtain a compound of Formula 6
;

(v) reducing the keto group in the compound of Formula 6 to obtain a compound of Formula 7
;

(vi) reacting the compound of Formula 7 with 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid to obtain a compound of Formula 8
;

(vii) reacting the compound of Formula 8 with methyl bromide to obtain a compound of Formula 9
;
(viii) deprotecting the compound of Formula 9 to obtain a compound of Formula 10:
; and
(ix) epoxide formation in the compound of Formula 10 to obtain tiotropium bromide of Formula 1.
In some embodiments of the process described above, the protecting group is benzyl, para-methoxy benzyl, p-nitrophenyl, or trityl. In some embodiments of the process described above, the protecting group is benzyl.
In some embodiments of the process described above, the reduction of step (ii) is carried out in the presence of sodium borohydride. In some of such embodiments, the reduction is carried out at a temperature of about 50 oC to about 70 oC.
In some embodiments of the process described above, the oxidation in step (iii) is a carried out in the presence of dimethyl sulfoxide, oxalyl chloride and triethylamine. In other embodiments of the process described above, the oxidation in step (iii) is carried out in the presence of bis(acetoxy)iodobenzene (BAIB) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO).
In some embodiments of the process described above, the condensing in step (iv) is carried out in refluxing alcohol. In some of such embodiments, the alcohol is methanol, ethanol, propanol, isopropanol or butanol, or a combination thereof.
In some embodiments of the process described above, the reduction in step (v) is carried out in the presence of sodium borohydride. In some of such embodiments, the reduction is carried out at a temperature of about 50 oC to about 70 oC.
In some embodiments of the process described above, the deprotection is carried out by hydrogenation.
In some embodiments of the process described above, the epoxide formation is carried out in the presence of diisopropyl azodicarboxylate (DIAD and triphenylphosphine.
Also provided herein is a process for the synthesis of a compound of Formula 8 comprising

(i) protecting a compound of Formula 2 to obtain a compound of Formula 3

wherein Bn is a protecting group;

(ii) reducing the compound of Formula 3 to a compound of Formula 4
;

(iii) oxidizing the compound of Formula 4 to a compound of Formula 5
;

(iv) condensing the dialdehyde of Formula 5 with acetone-1,3-dicarboxylic acid and methyl amine to obtain a compound of Formula 6
;

(v) reducing the keto group in the compound of Formula 6 to obtain a compound of Formula 7
;

(vi) reacting the compound of Formula 7 with 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid to obtain the compound of Formula 8.

In an aspect, provided herein is a process for the synthesis of scopine comprising
(i) protecting a compound of Formula 2 to obtain a compound of Formula 3

wherein Bn is a protecting group;

(ii) reducing the compound of Formula 3 to a compound of Formula 4
;

(iii) oxidizing the compound of Formula 4 to a compound of Formula 5
;

(iv) condensing the dialdehyde of Formula 5 with acetone-1,3-dicarboxylic acid and methyl amine to obtain a compound of Formula 6
;

(v) reducing the keto group in the compound of Formula 6 to obtain a compound of Formula 7
;

(vi) protecting the hydroxyl group in the compound of Formula 7 with an ester protecting group to obtain a compound of Formula 11:
Formula 11

wherein R is methyl, vinyl, phenyl and di(thiophen-2-yl)methanol;

(vii) removing the protecting group Bn in the compound of Formula 11 to obtain a compound of Formula 12:
Formula 12;

(viii) epoxide formation in the compound of Formula 12 obtain a compound of Formula 13
Formula 13; and

(ix) deprotection of the ester protecting group in the compound of Formula 13 to obtain scopine of Formula 14
Formula 14.

Detailed description of the invention:
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
In general aspect, the present invention provides a process for preparing tiotropium bromide and intermediates thereof. The process of the present invention is a synthetic, eco-friendly, non- hazardous and cost effective process.
The process described herein utilizes dialkyl tartarate as a starting material for the synthesis of scopine and tiotropium bromide via a double Mannich reaction (Robinson-Schopf reaction). The use of 2,3-Bis(benzyloxy)succinaldehyde in a Robinson-Schopf reaction, as for the process described herein, has not been disclosed previously.
An embodiment of the present invention relates to a process for preparing tiotropium bromide of Formula 1. The process comprises benzylating (+)-dimethyl tartrate of Formula 2 with benzyl bromide to form dimethyl dibenzyltartarate of Formula 3. Further, dimethyl dibenzyltartarate of Formula 3 is reduced using sodium borohydride in the presence of a solvent to form diol compound of Formula 4. The solvent is selected from alcohols such as ethanol, methanol, propanol, isopropanol and butanol. Other reducing agents such as Lithium aluminium hydride are contemplated within the scope of embodiments presented herein.
In a next step, the diol compound of Formula 4 is oxidised to form a dialdehyde compound of Formula 5. In an embodiment, the reaction is carried out under Swern conditions using dimethyl sulfoxide and oxalyl chloride in the presence of dry dichloromethane. In another embodiment, diol compound of Formula 4 is oxidised using bis(acetoxy)iodobenzene (BAIB) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to form dialdehyde compound of Formula 5. Other methods of oxidation such as o-iodoxybenzoic acid (IBX) mediated oxidation are also contemplated within the scope of embodiments presented herein.
In the next step, the dialdehyde compound of Formula 5 is condensed by Mannich reaction using methylamine hydrochloride and acetone-1,3-dicarboxylic acid to form tropinone compound of Formula 6. In the next step, tropinone compound of Formula 6 is reduced using sodium borohydride in the presence of a solvent to form secondary alcohol compound of Formula 7. The solvent is selected from alcohols such as ethanol, methanol, propanol, isopropanol and butanol.
In a further step, the compound of Formula 7 is esterified by Steglich esterification using 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid, dicyclohexylcarbodiimide and p-dimethylaminopyridine to form ester compound of Formula 8. Other suitable methods of esterification are also contemplated with the scope of embodiments presented herein. In the next step, the ester compound of Formula 8 is reacted with methyl bromide in the presence of a solvent to form a quaternary ammonium salt of Formula 9. The solvent is selected from alcohols such as ethanol, methanol, propanol and butanol.
In a further step, the quaternary ammonium salt of Formula 9 is debenzylated using palladium on carbon (Pd/C) in the presence of ethyl acetate to form a diol compound of Formula 10. In the next step, the diol compound of Formula 10 is reacted with diisopropyl azodicarboxylate (DIAD) and and triphenylphosphine to form compound of Formula 1. In addition to a Mitsunobu-type reaction for formation of the expoxide, other methods of etherification may be suitable and are contemplated within the scope of embodiments presented herin.
The reaction scheme of preparing compound of Formula 1 is represented below:

Further, the synthetic scheme provided above may be suitably modified for the synthesis of scopine. The hydroxy moiety in the compound of Formula 7 may be esterified with a suitable protection group, followed by removal of the Bn protecting group, optionally quarternization of the amine, and epoxide formation. Ester hydrolysis deprotection then furnishes scopine as free base or, optionally as a quarternary salt.
EXAMPLES
The following examples illustrate the invention, but are not limiting thereof.
Example 1: Benzylation of (+)-diethyl tartarate
A mixture of (+)-dimethyl tartrate 5.0 gm (1.0 equiv) and benzyl bromide 6.68 ml (2.0 equiv) in dichloromethane (70 mL) was treated with silver oxide 14.31gm (2.2 equiv) and allowed to stir for 12 h at room temperature. The mixture was filtered through Celite® and washed with dichloromethane. The filtrate was concentrated to dryness on the rotary evaporator. The residue was subjected to silica gel chromatography to obtain dimethyl dibenzyltartarate compound of Formula 3 as a colourless syrup.
Example 2: Reduction of diester to alcohol
To a solution of dimethyl dibenzyltartarate 10 gm (1 mmol) in 100 mL of ethanol, sodium borohydride 4.2 gm (4 equiv) was added and the mixture was stirred at 60 °C for 12 h. After completion, as monitored by TLC, the reaction mixture was allowed to cool and then ethanol was evaporated under reduced pressure. The residue was dissolved in 250 mL of water and the solution was neutralized using acetic acid. The product was extracted using diethyl ether (2 x 300 mL) and the combined ether extract was evaporated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:n-hexane, 2:8) to obtain the diol compound of Formula 4.
Example 3A: Oxidation of diol to dialdehyde (Swern Conditions)
Dimethyl sulfoxide18.75 ml (4 equiv) was added in a dropwise manner to a stirred solution of oxalyl chloride 11.54 ml (2 equiv) in dry DCM (80 mL) at -78 °C. After 30 min, a solution of primary alcohol 10 gm (1 equiv, in 80 mL of DCM) was added over 15 min. After 45 min, Et3N 55.35 ml (6 equiv) was added and then the mixture was allowed to warm to room temperature for additional 1 h. After completion of the reaction as per TLC, the mixture was poured into water (300 mL) and extracted with Et2O (300 mL, thrice). The combined organic extracts were washed with brine solution (200 mL), dried over MgSO4 and concentrated in vacuo. The resulting aldehyde compound of Formula 5 was used in next step without further purification.
Example 3B: Oxidation of diol to dialdehyde
To a solution of diol (0.5 mmol) in CH2Cl2 (10 mL) at 0 °C was added BAIB (0.55 mmol) and TEMPO (0.05 mmol). The mixture was stirred for 2 h at room temperature and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (hexanes/EtOAc, 9:1) to obtain dialdehyde compound of Formula 5 as a colorless liquid.
Example 4: Tropinone Synthesis via Mannich condensation
To a mixture of dialdehyde 10 gm (1 equiv), methylamine hydrochloride (1.2 equiv) and acetone-1,3-dicarboxylic acid 3.26 ml (1 equiv) was heated under reflux in methanol. After stirring the mixture under nitrogen for 24 h, conc. hydrochloric acid was added and then the solution was heated on the water bath for 1 h for complete decarboxylation. The solution was cooled to room temperature and then treated with a solution of NaOH (75%). The basic mixture was extracted with dichloromethane, dried over sodium sulfate, concentrated to about 50% solution and then filtered through a layer of alumina. The column was eluted with DCM and eluted liquid was concentrated under reduced pressure to obtain tropinone compound of Formula 6.
Example 5: Reduction of ketone to secondary alcohol
To a solution of tropinone 10 gm (1 equiv) in 100 mL of ethanol, sodium borohydride 0.54 gm (0.5 equiv) was added and the reaction mixture was stirred at 60 °C for 12 h. Upon completion of the reaction, as monitored by TLC, the reaction mixture was allowed to cool and then ethanol was evaporated under reduced pressure. The residue was dissolved in 250 mL of water and the solution was neutralized using acetic acid. The product was extracted using diethyl ether (2 x 200 mL) and the combined ether extracts was evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate: n-hexane, 2.5: 7.5) to give the pure alcohol compound of Formula 7.
Example 6: Esterification of alcohol with Acid (Steglich esterification)
A solution of 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid 6.79 gm (1.0 equiv) in dry dichloromethane were added DCC 5.84 gm (1.2 equiv) and p-dimethylaminopyridine 1.72 gm (0. 5 equiv). The resulting mixture was stirred at 0 °C for 10 min and then a solution of alcohol 10 gm (1.0 equiv) was added at the same temperature and the mixture was stirred for 3 h at room temperature. The precipitated dicyclohexylurea was removed by filtration through a fritted Büchner funnel. The filtrate was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane, 2:8) to give the pure ester compound of Formula 8.
Example 7: Quaternary ammonium salt formation
A solution of pure ester 10 gm (1 equiv) in 100 mL of absolute ethanol was added slowly to a solution of methyl bromide 1.14 ml (1.2 equiv) in ethanol under inert atmosphere. After complete addition (30 min), the solution was heated under reflux on water bath for 30 min. The product was separated by suction filtration, washed with two 100-mL of anhydrous ether and dried in air at room temperature to yield the quaternary ammonium salt compound of Formula 9.
Example 8: Debenzylation using Pd/C
To a solution of quaternary ammonium salt compound 10 gm in ethyl acetate was added Pd/C 0.3 gm and it was stirred under H2 atmosphere. After completion, the mixture was filtered through a short plug of Celite and rinsed thoroughly with EtOAc. The filtrate was concentrated in vacuo and purified by chromatography (silica gel, 60% EtOAc/n-hexane) to give the diol compound of Formula 10.
Example 9: Epoxide formation
To a mixture of diol 10 gm (0.5 equiv) were added diisopropyl azodicarboxylate (DIAD) 4.01 ml (1 equiv) and triphenylphosphine 5.34 gm (1 equiv) in anhydrous THF (15 mL) at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 24 h. After completion of the reaction as monitored by TLC, the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers was washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, 0–8% EtOAc/n-hexane) to give the compound of Formula 1.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

,CLAIMS:

1. A process for manufacture of tiotropium bromide of Formula 1 comprising

(i) protecting a compound of Formula 2 to obtain a compound of Formula 3

wherein Bn is a protecting group;

(ii) reducing the compound of Formula 3 to a compound of Formula 4
;

(iii) oxidizing the compound of Formula 4 to a compound of Formula 5
;

(iv) condensing the dialdehyde of Formula 5 with acetone-1,3-dicarboxylic acid and methyl amine to obtain a compound of Formula 6
;

(v) reducing the keto group in the compound of Formula 6 to obtain a compound of Formula 7
;

(vi) reacting the compound of Formula 7 with 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid to obtain a compound of Formula 8
;

(vii) reacting the compound of Formula 8 with methyl bromide to obtain a compound of Formula 9
;
(viii) deprotecting the compound of Formula 9 to obtain a compound of Formula 10:
; and
(ix) epoxide formation in the compound of Formula 10 to obtain tiotropium bromide of Formula 1.
2. The process of claim 1, wherein the protecting group is benzyl, para-methoxy benzyl, p-nitrophenyl, or trityl.
3. The process of claim 1, wherein the protecting group is benzyl.
4. The process of claim 1, wherein the reduction of step (ii) is carried out in the presence of sodium borohydride.
5. The process of claim 4, wherein the reduction is carried out at a temperature of about 50 oC to about 70 oC.
6. The process of claim 1, wherein the oxidation in step (iii) is a carried out in the presence of dimethyl sulfoxide, oxalyl chloride and triethylamine.
7. The process of claim 1, wherein the oxidation in step (iii) is carried out in the presence of bis(acetoxy)iodobenzene (BAIB) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO).
8. The process of claim 1, wherein the condensing in step (iv) is carried out in refluxing alcohol.
9. The process of claim 8, wherein the alcohol is methanol, ethanol, propanol, isopropanol or butanol, or a combination thereof.
10. The process of claim 1, wherein the reduction in step (v) is carried out in the presence of sodium borohydride.
11. The process of claim 10, wherein the reduction is carried out at a temperature of about 50 oC to about 70 oC.
12. The process of claim 1, wherein the deprotection is carried out by hydrogenation.
13. The process of claim 1, wherein the epoxide formation is carried out in the presence of diisopropyl azodicarboxylate (DIAD and triphenylphosphine.
14. A process for the synthesis of a compound of Formula 8 comprising

(i) protecting a compound of Formula 2 to obtain a compound of Formula 3

wherein Bn is a protecting group;

(ii) reducing the compound of Formula 3 to a compound of Formula 4
;

(iii) oxidizing the compound of Formula 4 to a compound of Formula 5
;

(iv) condensing the dialdehyde of Formula 5 with acetone-1,3-dicarboxylic acid and methyl amine to obtain a compound of Formula 6
;

(v) reducing the keto group in the compound of Formula 6 to obtain a compound of Formula 7
;

(vi) reacting the compound of Formula 7 with 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid to obtain the compound of Formula 8.

15. A process for the synthesis of scopine comprising
(i) protecting a compound of Formula 2 to obtain a compound of Formula 3

wherein Bn is a protecting group;

(ii) reducing the compound of Formula 3 to a compound of Formula 4
;

(iii) oxidizing the compound of Formula 4 to a compound of Formula 5
;

(iv) condensing the dialdehyde of Formula 5 with acetone-1,3-dicarboxylic acid and methyl amine to obtain a compound of Formula 6
;

(v) reducing the keto group in the compound of Formula 6 to obtain a compound of Formula 7
;

(vi) protecting the hydroxyl group in the compound of Formula 7 with an ester protecting group to obtain a compound of Formula 11:
Formula 11

wherein R is methyl, vinyl, phenyl and di(thiophen-2-yl)methanol;

(vii) removing the protecting group Bn in the compound of Formula 11 to obtain a compound of Formula 12:
Formula 12;

(viii) epoxide formation in the compound of Formula 12 obtain a compound of Formula 13
Formula 13; and

(ix) deprotection of the ester protecting group in the compound of Formula 13 to obtain scopine of Formula 14
Formula 14;