FIELD OF THE INVENTION

The invention relates to the field of organic chemistry and more particularly to synthetic process for the preparation of 3-Quinuclidinone HCl by recycling of 3S-Quinuclidinol in one step sequence of oxidation process. The developed oxidation procedure affords nearly quantitatively yield in the conversion of 3-S-Quinuclidinol(II) into 3- Quinuclidinone (III)

BACKGROUND OF THE INVENTION

3-R quinuclidinol (I) can be obtained by kinetic resolution of racemic mixtures of R- and S-3- quinuclidinol(ll). 3-R-Quinuclidinol (R-l-azabicyclo[2,2,2]octan-3-ol)(I) is used as a building block in the synthesis of muscarine Ml and M3 agonists as well as for muscarine M3 antagonists. See for example the recent review by Broadley and Kelly concerning muscarinic receptor agonist and antagonist. Talsaclidine fumarate (WAL 2014 FU) cevimeline HCl, and YM 905 are all examples of products where 3-R quinuclidinol (I) constitutes an integral part of the molecular entity. These products have shown potential in the treatment of Alzheimer's disease, Sjogren syndrome, and urinary incontinence, respectively. 3-R quinuclidinol (I) constitutes therefore a highly valuable building block for the synthetic production of several important pharmaceutical chemicals. Thus, in this context, need to reduce cost of process by recycling 3-S- Quinuclidinol (II). Process for recycling of 3-S-Quinuclidinol by using TEMP0(2,2,6,6- tetramethylpiperidin-l-oxyl radical and molecular chlorine and have been described ( Organic Process Research &Development 2002, 6, 197-200). All these prior art methods require expensive reagents, low temperatures and tedious procedures.

Therefore there exists a need for an improved reproducible process that is amenable to scale-up. This invention provides a simple and industrially viable process for the synthesis of 3-Quinuclidinone (III) from 3-S-Quinuclidinol (H).

SUMMARY OF THE INVENTION

Accordingly the invention provides a simple and industrially viable process for the synthesis of S-Quinuclidinone (III) from 3-S-Quinuclidinol (II).

The invention provides a process involving the recycling of the side-stream of 3-S quinuclidinol (II) in a two step-sequence oxidation and reduction process. The first step is constituted of the kinetic resolution process of R- and 3-S quinuclidinol (IV) indicated as pathway (a) in Scheme 1. The side stream of 3-S quinuclidinol (II) is according to the process sketch submitted for oxidation following pathway(b) to give 3-quinuclidinone( III). In the subsequent step, the ketone III can undergo a simple reduction, following pathway(c), thus providing a reacemic mixture of R-and S-3- quinuclidinol (IV).

In one aspect the invention provides a process for the synthesis of 3-Quinuclidinone (III). The said process comprises of decomposition of compound of formula VII in the presence of base in Scheme II

In another aspect the invention provides a process for preparing a compound of formula VII, said method comprises of reacting 3-S-Quinuclidinol (II) with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chlorosuccinamide; or thioanisole and N- bromosuccinamide in a suitable organic solvent or mixture thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for producing 3-Quinuclidinone (III), a key intermediate used in the synthesis of quinuclidinol based drugs.

One embodiment of this invention is directed to a method of producing 3-Quinuclidinone (III). The said method comprises of decomposition of compound of formula VII in the presence of base. The base used in the reaction with the compound of formula (VII) is an alkali metal alkoxide, or an alkali metal hydroxide or alkylamines. The alkoxide is preferably a CI -C6 alkoxide, more preferably a C1-C4 alkoxide, and most preferably a methoxide or ethoxide. The alkali metal is preferably lithium, sodium or potassium. The reaction temperature is suitably in the range from -25°C to about 10 C°.

In another embodiment this invention provides a process of synthesis of compound of formula VII (sulfoxonium complex) said method comprises of reacting 3-S- Quinuclidinol (II) with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chloro succinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent. The solvent used in the reaction of compound of formula VII is benzene, toluene, xylene, dioxane, tetrahydrofuan, chlorinated solvents or a mixture thereof. The reaction temperature is suitably in the range from about -25°C to about 10°C.

This invention provides a process for the oxidation of 3-S-Quinuclidinol (II) to 3- Quinuclidinone (III), which is operationally simple, highly selective, and efficient. This process would effectively allow an overall transformation such as: RR'CHOH + C12 ^RR'CO + 2HC1, which is mediated by a sulfide. The operability of this scheme has now been demonstrated. For example, treatment of dimethyl sulfide in carbon tetrachloride at 0°C with 1 equiv of chlorine in carbon tetrachloride at 0°C results in rapid formation of the partially insoluble complex V, which when cooled to -20 °C and treated with 3-S-Quinuclidinol (II) for 2 hr at -20°C with stirring is converted to the sulfoxonium complex VII. Addition of 2 equiv of triethylamine removal of the cooling bath, and isolation crude and further treated with IPA. HCl to afford pure 3- Quinuclidinone HCl (Ilia) in ca.80% yield .

The oxidation of 3-S-Quinuclidinol (II) can be effected even more cleanly and efficiently (85 % yield) using the reported complex VI from dimethyl sulfide and N- chlorosuccinimide under carefully controlled conditions.

Hereinafter, the invention is explained more specifically referring to the working examples, it being understood that the examples incur no restricting effect on the invention.

Example 1

Preparation of 3 -Quinuclidinone Hydrochloride (III a)

To a solution of 3-S-QuinucIidinol (50 g, 0.3937 mol) in dichloromethane (1 L) at -10°C to -15°C, dimethyl sulfide (51.4 g, 0.8267 mol) and diisopropyl ethylamine (66.15g, 0.5118 mol) were added in a single lot under argon and stirred for 15-30 min. N- Chlorosuccinamide (157.7 g, 1.181 mol) was added lot wise over the while maintaining the internal temperature at -10°C to -15°C. The reaction mixture was stirred for 3 hr at - IO°C to -15°C. Completion of reaction was monitored by Gas Chromatography (GC). After completion of reaction, dilute Sodium hydroxide solution (35 g in 600 mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°C and stirred for 1 hr at 20°C. The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane (200ml x 3). Product from organic layer was distill off completely under vacuum. To the residue charged isopropyl alcohol 300ml and stirred for 15min.Cool to 10-15 deg and slowly added IPA.HCL 50ml to get PH (1-2). Stirred for thr. Filtered the reaction mass and washed with isopropyl alcohol (100ml). Weight 50 gr (79%).

EXAMPLE-2

Preparation of 3 -Quinuclidinone Hydrochloride (IIIa)

To a solution of 3-S-Quinuclidinol (50 g, 0.3937 mol) in dichloromethane (1 L) at -10°C to -15°C, dimethyl sulfide (51.4 g, 0.8267 mol) and Triethylamine (51.78g, 0.5118 mol) were added in a single lot under argon and stirred for 15-30 min. N-Chlorosuccinamide (157.7 g, 1.181 mol) was added lot wise over 1hr while maintaining the internal temperature at -10°C to -15°C. The reaction mixture was stirred for 3 hr at -10°C to - 15°C. Completion of reaction was monitored by Gas Chromatography (GC). After completion of reaction, dilute Sodium hydroxide solution (35 g in 600 mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°C and stirred for 1 hr at 20°C. The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane (200ml x 3). Product from organic layer was distill off completely under vacuum. To the residue charged isopropyl alcohol 300ml and stirred for 15min.Cool to 10-15 deg and slowly added IPA.HCL 50ml to get PH (l-2).Stirred for 1hr. Filtered the reaction mass and washed with isopropyl alcohol (100ml).

Weight ; 30 gr (47%)

EXAMPLE-3

Preparation of 3 -Quinuclidinone Hydrochloride (IIIa)

To a solution of N-Chlorosuccinamide (10.51 g, 0.0787mol) in carbon tetrachloride( 100ml) at -10°C, a solution of thioanisole (9.76 g, 0.0787 mol) of in dichloromethane(20ml) was added under argon. A white precipitate appeared immediately after addition of the sulfide. The mixture was cooled to -20°C, and a solution of 3 -Quinuclidinol (5 g, 0.0394 mol) in dichloromethane (25ml) was added dropwise. Stirring was continued for 2hrs at -20°C, and then a solution of triethylamine (7.9 g,, 0.0787 mol) in dichloromethane(25ml) was added dropwise. After completion of reaction, dilute Sodium hydroxide solution (3.5 g in 60 mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°C and stirred for 1 hr at 20°C. The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane (20ml x 3), Product from organic layer was distill off completely under vacuum. To the residue charged isopropyl alcohol 30ml and stirred for IS min. Cool to 10-15 deg and slowly added IPA.HCL 5ml to get PH (1- 2).Stirred for 1hr.Filtered the reaction mass and washed with isopropyl alcohol (10ml). Weight 1.5gr(24%)

Example 4

Preparation of 3 -Quinuclidinone Hydrochloride(IIIa)

To a solution of 3-S-Quinuclidinol (50 g, 0.3937 mol) in dichloromethane (I L) at -10°C to -15°C, dimethyl sulfide (51.4 g, 0.8267 mol) and diisopropyl ethylamine (66.15g, 0.5118 mol) were added in a single lot under argon and sfirred for 15-30 min. Slowly passed chlorine gas(83.8g, 1.181 mol)for 3hrs while maintaining the internal temperature at -10°C to -15°C. The reaction mixture was stirred for 3 hr at -10°C to -15°C. Complefion of reaction was monitored by Gas Chromatography (GC). After completion of reaction, dilute Sodium hydroxide solution (35 g in 600 mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°C and stirred for 1 hr at 20°C. The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane (200ml x 3). Product from organic layer was distill off completely under vacuum. To the residue charged isopropyl alcohol 300ml and stirred for 15min.Cool to 10-15 deg and slowly added IPA.HCL 50ml to get PH (1- 2).Stirred for 1hr.Filtered the reaction mass and washed with isopropyl alcohol (100ml). Weight : 35 gr ( 56%)

We claim

1. A method for preparing a compound of formula (III):

wherein the said process comprises of decomposition of compound of formula VII in the presence of base.

2. The process according to claim 1, wherein compound of formula VII is formed by reacting 3-S-Quinuclidinol(II) with

- dimethylsulfide and N-chlorosuccinamide; or

- dimethylsulfide and N-bromosuccinamide; or

- dimethylsulfide and chlorine gas; or

- thioanisole and N-chlorosuccinamide; or

- thioanisole and N-bromosuccinamide); or

- thioanisole and chlorine gas;

3. The process according to claim 2, wherein said reaction is carried out in the presence of a solvent.

4. The process according to claim 3, wherein the said solvent is Dioxane, THF, chlorinated solvents or a mixture thereof.

5. The process according to claim 2, wherein the reaction is carried out at a temperature in the range from about -25°C to about 10°C.

6. The process according to claim 1, wherein said base is an alkali metal alkoxide, or an alkali metal hydroxide or alkylamines.

7. The process according to claim 6, wherein said alkali metal is Lithium, Sodium or Potassium.

8. The process according to claim 1, wherein the reaction with the compound of formula VII is carried out at a temperature in the range from about -25°C to about 20 C°.