Field of the Invention

The present invention relates to an improved process for producing an optically active quinuclidinol. More preferably, the present invention provides process for preparation of optically active quinuclidinol by resolution of racemic 3-quinuclidinol using a chiral acid.

Background of the Invention

Quinuclidinol is an aza bicyclic compound, chemically known as l azabicyclo [2.2.2]octan-3-ol and is structurally represented as given below : N The optically active form of Quinuclidinol is used as an important intermediate for various pharmaceutically active ingredients such as Solifenacin, Palonosetron, Talsaclidine, Revatropate, Cevimeline etc. J. Am. Chem. Soc. 74, 2215-2218(1952) discloses a resolution process of racemic Quiniclidinol where a diastereomeric salt of (R)- 3-quinuclidinol with (S)-camphorsulfonic acid in a solution of propanol/acetone was prepared. German Pat. No. 19715465 discloses a process for a preparing optically active 3-quinuclidinol by reacting racemic 3-quinuclidinol with subtilisin protease, wherein only (S) form is converted to (S)-3-quinuclidinyl butyric acid, so that (R) form is prepared. Life Sci. 21(9), 1293-302 (1977) discloses a production method of optically active 3-quinuclidinol which comprises selective asymmetric hydrolysis of (R)-3-quinuclidinol ester by contacting horse serum esterase with the racemate of 3-quinuclidinol ester.

Acta. Pharm. Suec. 16(4), 281-3 (1979) discloses an alternative method for the preparation of optically active 3-quinuclidinol by optical resolution of the acetylated form of racemic 3-quinuclidinol with tartaric acid, followed by hydrolysis. Synth. Commun. 22(13), 1895-911, (1992) discloses another method for the preparation of optically active 3-quinuclidinol comprising reacting 3-quinuclidinone with an optically active phenethylamine reducing the imine thus formed with sodium borohydride. U.S. Pat. No. 5,215,918 describes a process utilizing microorganisms and enzymes in the preparation of optically active (R)-3-quinuclidinol, which comprises reacting racemic 3-quinuclidinol ester with microorganisms and enzymes for selective and asymmetric hydrolysis of (S)-3-quinuclidinol ester, so that the remaining (R)-3-quinuclidinol ester is hydrolyzed to obtain (R)-3-quinuclidinol. U.S. Pat. No. 5,744,606 describes a process for producing optically active 3-quinuclidinol by asymmetric hydrogenation of 3-quinuclidinone adduct with a Lewis acid or an ammonium salt thereof or the like in the presence of a rhodium-optically active phosphine complex. Research on synthesis of (R)-3-quinuclidinol (http://www.12340000.com/science-engineering-b/organic-chemical-industry/39714.html) discloses preparation of optically active 3-quinuclidinol by resolution of racemic 3-quinuclidinol with L-tartaric acid.

Most of the known processes include a process for preparing optically active 3-quinuclidinol from 3-quinuclidinone using asymmetric reductive reaction by microorganisms and enzymes. In these reactions, wild-type microorganisms are reacted to substrate compounds to directly produce optically active compounds. These processes have problems such as low optical purity or difficulty in mass production due to complex synthetic processes. Hence, these methods are difficult in producing optically active quinuclidinol with commercial advantages in a simple and easy manner. Thus, none of the above processes are simple and economically efficient for the preparation of optically active quinuclidinol. There remains a need to provide an improved process for preparing optically active quinuclidinol, which is cost-effective, feasible and highly reproducible in a commercial manner with high yield and purity.

Objective of the Invention

The main objective of the present invention is to provide cost-effective and commercially feasible process for the preparation of quinuclidinol. Another objective of the present invention is to provide novel salts of quinuclidinol.

Summary of the Invention

Accordingly, the present invention provides an improved process for the preparation of optically pure or optically enriched enantiomers of 3-quinuclidinol of formula I,
N Formula-I wherein, R represents H, Halogen, linear or branched alkyl group, alkoxy group, a cycloaikyl or an aralkyl group substituted or unsubstituted, comprising: a) resolving racemic 3-quinuclidinol of formula III N Formula-Ill wherein, R is as described above, with a chiral acid selected from mandelic acid and tartaric acid derivatives to obtain salt of formula II. N Formula-I I wherein, X is the chiral acid; R is as described above; and b) converting the salt of formula II to yield optically active 3-quinuclidinol of formula I. In yet another aspect, the present invention provides novel salts of optically active 3-Quinuclidinol of formula II. N Formula-ll wherein, X is a chiral acid selected from mandelic acid and tartaric acid derivatives; R is as described above.

Detailed Description of the Invention

In an embodiment, the present invention provides an improved process for the preparation of optically pure or optically enriched enantiomers (R)-3-quinuclidinol or (S)-3-quinuclidinol of formula I N Formula-I wherein, R represents H, Halogen, linear or branched alkyl group, alkoxy group, a cycloalkyl or an aralkyl group substituted or unsubstituted. In an embodiment, the present invention provides a process for preparing (R)-3-quinuclidinol of formula la, N Formula-la comprising: a) resolving racemic 3-quinuclidinol of formula III N Formula-Ill with a chiral acid selected from mandelic acid and tartaric acid derivatives in a solvent to obtain a salt of (R)-3-quinuclidinol of formula Ha,^°; N Formula-lla

b) optionally purifying the compound of formula Ha; and

c) converting the salt of formula Ha to (R)-3 -quinuclidinol of formula la.

In an another embodiment, the present invention provides a process for preparing (S)-3-quinuclidinol of formula lb,
,vOH
R ,
Formula-lb comprising: a) resolving racemic 3-quinuclidinol of formula III
*&*
N Formula-Ill wherein, R is as described above, with a chiral acid selected from mandelic acid and tartaric acid derivatives in a solvent to obtain a salt of compound of formula lib,
R-, , , N
Formula-lib wherein, X is the chiral acid; R is as described above;

b) optionally purifying the compound of formula lib; and

c) converting the salt of formula lib to (S)-3-quinuclidinol of formula lb.

According to the present invention, the chiral acid that can be used for resolution of racemic 3-quinuclidinol of compound of formula III is selected from mandelic acid and tartaric acid derivatives such as S-(+) mandelic acid, R-(-) mandelic acid, (-)-dibenzoyl-L-tartaric acid, (-)-dibenzoyl-L-tartaric acid monohydrate, (+)-dibenzoyl-D-tartaric acid, (+)-dibenzoyl-D-tartaric acid monohydrate, (-)-dipara-toluoyl-L-tartaric acid, (-)-dipara-toluoyl-L-tartaric acid monohydrate, (+)-dipara-toluoyl-D-tartaric acid and (+)-dipara-toluoyl-D-tartaric acid monohydrate. Suitable organic solvent used for the resolution according to the present invention is selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and mixtures thereof or their aqueous mixtures.

The resolution process can be carried out at temperature range of about 0-100°C or reflux temperatures of the solvents used. The salt obtained in step a) is optionally purified by crystallization prior to its conversion to free base. Preferably, the purification is carried out in a solvent selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and mixtures thereof or their aqueous mixtures. The conversion of salt of formula II to optically active quinuclidinol is carried out by treating compound of formula Ha or lib with an acid, such as an inorganic acid, preferably hydrochloric acid.

In a preferred embodiment, the present invention provides a process for preparing (R)-3-quinuclidinol of formula la comprising:

a) resolving racemic 3-quinuclidinol of formula III with a chiral acid selected iromwith a chiral acid selected from mandelic acid and tartaric acid derivatives in a solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol or mixtures thereof to obtain a salt of R-3-quinuclidinol of formula Ha,

b) optionally purifying the compound of formula Ha,

c) converting the salt of compound of formula Ha to (R)-3-quinuclidinol of formula la by treating with an inorganic acid; and

d) isolating (R)-3-quinuclidinolin optically active form.

In another preferred embodiment, the present invention provides a process for preparing (S)-3-quinuclidinol of formula lb comprising:

a) resolving racemic 3-quinuclidinol of formula III with a chiral acid selected from with a chiral acid selected from mandelic acid and tartaric acid derivatives in a solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol or mixtures thereof to obtain a salt of (S)-3-quinuclidinol of formula lib,

b) optionally purifying the compound of formula lib,

c) converting the salt of compound of formula lib to (S)-3-quinuclidinol of formula lb by treating with an inorganic acid and

d) isolating (S)-3-quinuclidinolin optically active form.

In yet another embodiment, the present invention provides novel salts of optically active 3-quinuclidinol of formula II. «&: N Formula-ll wherein, X is the chiral acid selected from mandelic acid and tartaric acid derivatives; R is as described above. In yet another embodiment, the present invention provides novel salts (R)-3-quinuclidinol of formula Ha. N Formula-Ma wherein, X is the chiral acid selected from mandelic acid and tartaric acid derivatives; R is as described above. In yet another embodiment, the present invention provides novel salts (S)-3-quinuclidinol of formula Ha. *&: N Formula-lib wherein, X is the chiral acid selected from mandelic acid and tartaric acid derivatives; R is as described above.

In a preferred embodiment, the present invention provides novel dibenzoyl-D-tartrate salt of (R)-3-quinuclidinol of formula lie.
OH
.1/2 DBTA
Formula-llc
In yet another embodiment, the present invention provides novel (S)-3-
quinuclidinoldibenzoyl-L-tartrate of formula lid.
V£>H
.1/2 DBTA
Formula-lid In yet another embodiment the present invention provides a process for the preparation of (R)-3-quinuclidinoldibenzoyl-D-tartrate of formula lie comprising:

a) resolving racemic 3-quinuclidinol of formula III with (+)-dibenzoyl-D-tartaric acid monohydrate in a solvent to obtain a salt (R)-3-quinuclidinoldibenzoyl-D-tartrate of compound of formula lie, and

b) isolating (R)-3-quinuclidinoldibenzoyl-D-tartrate.

In yet another embodiment the present invention provides a process for the preparation of (S)-quinuclidinoldibenzoyl-L-tartrate of formula lid comprising:

a) resolving racemic 3-quinuclidinol of formula III with (-)-dibenzoyl-L-tartaric acid monohydrate in a solvent to obtain a salt (S)-3-quinuclidinoldibenzoyl-L-tartrate of compound of formula lid, and

b) isolating (S)-3-quinuclidinoldibenzoyl-L-tartrate.

In a more preferred embodiment, the present invention provides a process for the preparation of (R)-3-quinuclidinoldibenzoyl-D-tartrate of formula lie comprising:

a) resolving racemic 3-quinuclidinol of formula III with (+)-dibenzoyl-D-tartaric acid monohydrate in solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol or mixtures thereof, to obtain a salt (R)-3-quinuclidinoldibenzoyl-D-tartrate of compound of formula lie, and

b) isolating (R)-3-quinuclidinoldibenzoyl-D-tartrate.

In another preferred embodiment the present invention provides a process for the preparation of (S)-3-quinuclidinoldibenzoyl-L-tartrate of formula lid comprising:
«€f
«€)

a) resolving racemic 3-quinuclidinol of formula III with (-)-dibenzoyl-L-tartaric acid monohydrate in solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol or mixtures thereof, to obtain a salt (S)-3-quinuclidinoldibenzoyl-L-tartrate of compound of formula lid, and

b) isolating (S)-3-quinuclidinoldibenzoyl-L-tartrate.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale.

Example 1

Preparation of (RV3-quinuclidinol

To a mixture of (+)-dibenzoyl-D-tartaric acid monohydrate (150 g, 0.4mol) and methanol
(200 ml) was added 3-Quiniclidinol (100 g, 0.79 mol) and stirred the reaction mixture for
about 30 min. Heated the reaction mass to reflux temperature and maintaintcd at the same
temperature for about 3 hours. Cooled the reaction mass to 0-50°C and stirred for about 1 hr.
Filtered the salt of R-(3)-Quinuclidinoldibenzoyl-D-tartrate (130 g) thus obtained and
recrystallized using methanol (1000 ml) to obtain pure R-(3)-Quinuclidinoldibenzoyl-D-
tartrate (100 g). Optical rotation: +55 (C = 2% in methanol). R-(3)-Quinuclidinoldibenzoyl-D-tartrate was treated with water (100 ml) and HC1 (50 ml) and stirred for about 30 min. Extracted the reaction mass with ethyl acetate (2 X 500 ml) to recover dibenzoyl-D-tartaric acid and the aqueous layer was treated with NaOH.Ux'racted the aqueous layer with chloroform (4 X 200 ml), combined chloroform extracts were dried over sodium sulfate and evaporated the solvent completely to get white solid (40 g). R-(3)-Quinuclidinol obtained was purified by recrystallization from methanol and acetone (1:10) to get pure white crystals of R-(3)-Quinuclidinol (38 g). Optical rotation: -43.7 (C= 3% in IN HC1); 99.9% chiral purity by HPLC.

Example 2

Preparation of (S)-3-quinuclidinol

To a mixture of (-)-dibenzoyl-L-tartaric acid monohydrate (150 g, 0.4 mol) and methanol
(200 ml) was added 3-Quiniclidinol (100 g, 0.79 mol) and stirred the reaction mixture for
10 about 30 min. Heated the reaction mass to reflux temperature and maintained at the same temperature for about 3 hours. Cooled the reaction mass to 0-50°C and stirred for about 1 hr. Filtered the salt of (S)-3-Quinuclidinol dibenzoyl-L-tartrate (130 g) thus obtained and recrystallized using methanol (1000 ml) to obtain pure (S)-3-Quinuclidinol dibenzoyl-L-tartrate (100 g).

Optical rotation: -55 (C = 2% in methanol).

(S)-3-Quinuclidinol dibenzoyl-L-tartrate was treated with water (100 ml) and 1 :C1 (50 ml) and stirred for about 30 min. Extracted the reaction mass with ethyl acetate (2 X 500 ml) to recover dibenzoyl-L-tartaric acid and the aqueous layer was treated with NaOII. Extracted the aqueous layer with chloroform (4 X 200 ml), combined chloroform extracts were dried over sodium sulfate and evaporated the solvent completely to get white solid (!() g). (S)-3-Quinuclidinol obtained was purified by recrystallization from methanol and acetone (1:10) to get pure white crystals of (S)-3-Quinuclidinol (38 g). Optical rotation: +43.7 (C= 3% in IN HC1), 99.9% chiral purity by HPLC.

We Claim:

1. An improved process for preparing (R)-3-quinuclidinol of formula la,
N Formula-la wherein, R represents H, Halogen, linear or branched alkyl group, alkoxy group, a cycloalkyl or an aralkyl group substituted or unsubstituted, which process comprises:

a. resolving racemic 3-quinuclidinol of formula III N Formula-Ill wherein, R is as described above, with a chiral acid selected with a chiral acid selected from mandelic acid and tartaric acid derivatives in a solvent to obtain a salt of (R)-3-quinuclidinol of formula Ha,
^: N Formula-lla wherein, X is the chiral acid; R is as described above;

b. optionally purifying the compound of formula Ha; and

c. converting the salt of formula Ha to (R)-3-quinuclidinol of formula la.

2. An improved process for preparing (S)-3-quinuclidinol of formula lb,
N Formula-lb wherein, R represents H, Halogen, linear or branched alkyl group, alkoxy group, a cycloalkyl or an aralkyl group substituted or unsubstituted, which process comprises:

a. resolving racemic 3-quinuclidinol of formula III N Formula-Ill wherein, R is as described above, with a chiral acid selected from mandelic acid and tartaric acid derivatives in a solvent to obtain a salt of compound of formula lib, N Formula-lib wherein, X is the chiral acid; R is as described above;

b. optionally purifying the compound of formula lib; and

c. converting the salt of formula lib to (S)-3-quinuclidinol of formula lb.

3. The process according to claims 1 & 2, wherein the chiral acid used in step a) is selected from mandelic acid and tartaric acid derivatives such as S-(+) mandelic acid, R-(-) mandelic acid, (-)-dibenzoyl-L-tartaric acid, (-)-dibenzoyl-L-tartaric acid monohydrate, (+)-dibenzoyl-D-tartaric acid, (+)-dibenzoyl-D-tartaric acid monohydrate, (-)-dipara-toluoyl-L-tartaric acid, (-)-dipara-toluoyl-L-tartaric acid monohydrate, (+)-dipara-toluoyl-D-tartaric acid and (+)-dipara-toluoyl-D-tartaric acid monohydrate.

4. The process according to claims 1 & 2, wherein the solvent used in steps a) & b) is selected from alcohols such as methanol, ethanol, isopropyl alcohol or mixture thereof; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, propionitrile and mixtures thereof or their aqueous mixtures.

5. The process according to claims 1 & 2, wherein the conversion of salt of compounds of formulae 11a or lib to optically active (R) and (S) quinuclidinol is carried out by treating compounds of formulae Ha or lib with an acid such as inorganic acid and preferably hydrochloric acid.

6. Novel dibenzoyl-D-tartrate salt of (R)-3-quinuclidinol of formula lie.
OH
.1/2 DBTA Formula-llc

7. Novel (S)-3-quinuclidinoldibenzoyl-L-tartrate of formula lid.
"&-
,%xOH .1/2 DBTA
Formula-lid

8. A process for the preparation of (R)-3-quinuclidinoldibenzoyl-D-tartrate of formula lie comprising:

a. resolving racemic 3-quinuclidinol of formula III with (+)-dibenzoyl-D-tartaric acid monohydrate in a solvent to obtain a salt (R)-3-quinuclidinoldibenzoyl-D-tartrate of compound of formula lie, and

b. isolating (R)-3-quinuclidinoldibenzoyl-D-tartrate.

9. A process for the preparation of (S)-quinuclidinoldibenzoyl-L-tartrate of formula lid comprising:

a. resolving racemic 3-quinuclidinol of formula III with (-)-dibenzoyl-L-tartaric acid monohydratein a solvent to obtain a salt (S)-3-quinuclidinoldibenzoyl-L-tartrate of compound of formula lid, and

b. isolating (S)-3-quinuclidinoldibenzoyl-L-tartrate.

10. The process according to claims 9 & 10, wherein the solvent used in steps a) is selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof.