DESC:This application claims priority to Indian Provisional Patent Application No. 201741006241 filed on 22 February 2017, which is incorporated herein in its entirety.
FIELD OF INVENTION
This disclosure is related to a process for manufacture of tiotropium bromide monohydrate.
BACKGROUND OF THE INVENTION
Tiotropium bromide monohydrate 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 monohydrate, is an anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease.
Tiotropium bromide monohydrate has been synthesized via N-demethylated tiotropium which was obtained by a reaction of methyl di(2-thienyl)glycolate and scopine using sodium metal in melt or sodium hydroxide in melt. However the use of sodium metal melt or sodium hydroxide in melt is not suitable for industrial scale manufacturing.
There is still a need for methods of synthesis of tiotropium bromide monohydrate which utilize reagents or conditions which are eco-friendly, non- hazardous and cost effective, and are suitable for industrial scale production.
SUMMARY OF THE INVENTION
Provided herein is a process for synthesis of tiotropium bromide monohydrate wherein the coupling of scopine with 2, 2-dithienyl glycolate is achieved as a two step process under mild conditions.
Described herein is a process for synthesis of tiotropium bromide monohydrate. The process for synthesis of tiotropium bromide monohydrate comprises the steps of:
(A) coupling of scopine with 2, 2 dithienyl glycolate, the process comprising:
(i) reaction of scopine (1) with methyl chlorooxoacetate (2) to provide a dioxalate intermediate having the structure (3);

and (ii) a Grignard reaction of the dioxalate intermediate of structure (3) with 2-bromothiophene (4) to provide an intermediate of structure (5);
.
(B) then converting of 5 to tiotropium bromide (6) by N-methylation of the intermediate of structure (5) with a methyl halide (e.g. methyl bromide), to obtain tiotropium bromide as a monohydrate.
DETAILED DESCRIPTION OF THE INVENTION
All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.
Described herein is a process for preparation of tiotropium bromide monohydrate and intermediates thereof. In one embodiment, provided herein is a process for coupling of scopine with 2, 2 dithienyl glycolate, the process comprising:
(ii) reaction of scopine (1) with methyl chlorooxoacetate (2) to provide a dioxalate intermediate having the structure (3);

and (ii) a Grignard reaction of the dioxalate intermediate of structure (3) with 2-bromothiophene (4) to provide an intermediate of structure (5)
.
The reaction of scopine (1) with methyl chlorooxoacetate (2) is conducted at about 0 oC although other possible temperatures are readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein. The reaction is conducted in aprotic solvents such as dichloromethane (DCM), dichloroethane (DCE), chloroform, tetrahydrofuran (THF) and the like, preferably in DCM. Other reagents may be used instead of methyl chlorooxoacetate including and not limited to other alkyl halooxoacetate, (e.g., ethyl chlorooxoacetate and the like).
The Grignard reaction of the dioxalate intermediate of structure (3) with 2-bromothiophene (4) is initiated at ambient temperature, although other higher or lower temperatures will be readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein.
Advantageously, the two steps shown above are conducted under mild conditions while the epoxide remains intact. In other words, an extra step for introduction of the epoxide is not required in the process described herein.
It will be appreciated that other methods for synthesis of compound 3 from scopine are possible including the reactions of oxalic acid monomethyl ester and dimethyl oxalate with scopine in the presence of suitable coupling reagents as shown below. Such reactions are also contemplated as alternate embodiments for step (i).

In an embodiment, the process further comprises N-methylation of the intermediate of structure (5) with a methyl halide, preferably methyl bromide monohydrate. The reaction is conducted in an aprotic solvent such as acetonitrile, THF, chloroform and the like, preferably in a mixture of acetonitrile and chloroform.

EXAMPLES

STEP I - Acylation of Scopine (1) with methyl chlorooxoacetate (2)

To a stirred solution of scopine (1, 1 equiv) in dichloromethane was added methyl chlorooxoacetate (2, 1.1 equiv) at 0 oC under nitrogen atmosphere for 10 min. The resulting solution was allowed to stir at room temperature over 12h. Removal of the solvent under reduced pressure followed by washing with diethyl ether afforded the product (3) as a white solid.

STEP II - Grignard reaction of (3) with 2-bromothiophene (4)

To a suspension of 2-bromothiophene (4, 2.2 equiv) and Mg metal (2.2 equiv) in THF (15 mL) was added 1,2-dibromoethane to initiate the reaction. The remaining solution was added over a period of 30 min. After stirring for 1h, diester 3 (1 equiv) was added in portions over a period of 30 min. Upon completion, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in vacuo. The resulting residue was purified by crystallization to afford the product (5) as a white solid.

STEP III - N-Alkylation of (5) with methyl bromide monohydrate

A solution of compound 5 (1 equiv) in acetonitrile and chloroform mixture (10 mL, 1:1) was treated with bromomethane gas (4 equiv). The resulting mixture was stirred at room temperature. After 48h, the solution was filtered and the residue was dissolved in water (2.5 volumes) and heated up to 90 ?C until it becomes clear solution, which was then treated with activated charcoal. The solution was filtered, washed with 0.5 mL of water and cooled to 5 ?C, then filtered and washed with diethyl ether/acetone to afford the pure monohydrate (6) as a white solid. The product (6) is isolated as a monohydrate as evidenced by the presence of moisture content between 2.5%-4.0% measured by Karl Fisher test as per EP [tiotropium bromide monohydrate].

The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
,CLAIMS:
1. A process for preparation of tiotropium bromide monohydrate (6) comprising:
(i) reaction of scopine (1) with methyl chlorooxoacetate (2) to provide a dioxalate intermediate having the structure (3);

and
(ii) a Grignard reaction of the dioxalate intermediate of structure (3) with 2-bromothiophene (4) to provide an intermediate of structure (5)
.

2. The process of claim 1, wherein step (i) is conducted in dichloromethane.
3. The process of claim 1, wherein step (i) is conducted at a temperature of 0 oC
4. The process of claim 1, further comprising N-methylation of the intermediate of structure
(5) with a methyl halide.
5. The process of claim 4, wherein the methyl halide is methyl bromide monohydrate.
6. The process of claim 4, wherein the solvent is a mixture of acetonitrile and chloroform.
7. The process of claim 1, wherein the of moisture content of the tiotropium bromide
monohydrate (6) is between 2.5%-4.0%.