| EP0280603A1 | 1988-08-31 | |||
| EP0099789A1 | 1984-02-01 |
Chimiko-farmacevticeskij zurnal, Vol. 7, No. 8, 1973, MIKHLINA, E.E. et al.: "Synthesis and pharmacological study of 3-hydroxy- and 3-aminoquinuclidine derivatives", see page 20 - page 24, and the whole document, particularly compound XXII.
| 1. | Process of preparing optical active stereo isomeric forms of a racemic carboxylic acid amide of 3aminoquinuclidine of the formula I wherein R means H, CF3, CC13 or a straight or branched hydro¬ carbon chain of the general formula or CnH/2n+1) wherein one or several hydrogen atoms may be exchanged by halogen atoms F, Cl, Br or I, characterized in that a racemic aminoamidechiral acid salt of the formula (II) wherein R is as defined above and HA is the optical active acid is formed, the diastereomer salt is resolved in its optical active forms and the amide of formula (I) in the optical active form is released from the separated salt. |
| 2. | The process of claim 1, characterized in the use of S(+)camphor10sulphonic acid, R ()camphorlOsulphonic acid, D()tartaric acid, L(+) tartaric acid, D()αhydroxyphenylic acetic acid, L(+)α hydroxyphenylic acetic acid, D(+)malic acid, L()malic acid, (+)dibenzoylDtartaric acid or ()dibenzoylLtartaric acid as chiral acid HA in the salt (II). |
| 3. | The process of claim 1, characterized in R being H or CH3. |
| 4. | The processs of any of the preceeding claims, characterized in that the salts of the formula (II) are separated by fractionatal crystallisation. |
| 5. | Enantiomers of absolute configuration 3S of the amides of formula (I) . |
| 6. | Enantiomers of absolute confirmation of 3R of the amides of the formula (I) . |
| 7. | S()N(aminonuclidinyl3)acetamide. |
| 8. | R(+)N(aminoquinuclidinyl3)aetamide. |
| 9. | S()N(aminoquinuclidiny13)formamide. |
| 10. | R(+)N(aminoquinuclidinyl3)formamide. |
| 11. | Process of preparing S()3aminoquinuclidin or salts thereof, characterized by the hydrolysis of the compounds of claims 5,7 or 9. |
| 12. | Process of preparing R(+)3aminoquinuclidin or salts thereof, characterized by the hydrolysis of the compounds of claims 6, 8 or 10. |
The amides of optically active 3-aminoquinuclidine are useful precursors in the synthesis of certain gastrointestinal drugs.
From the French Patent Application 87.01355 it is known that resolution of racemic N-(guinuclidinyl-3)-chloro-3 benzamide with optically active tartaric acid yields the optically active benzamide in 32% yield from racemic benzamide. Subsequent hydrolysis of the optically active benzamide yields optically active 3-aminoquinuclidine dihydrochlorides.
The same patent also describes the asymmetric synthesis of optically active N-( -methyl-benzyl)-3-amino-quinuclidine dihydrochlorides and the subsequent hydrolysis of these compounds to yield optically active 3-aminoquinuclidine dihydrochlorides. However, these methods are time consuming, they give low yields and the products do not have the necessary optical purity.
The present invention provides a method for resolving a racemic carboxylic acid amide of 3-aminoquinuclidine of formula
(I)
H
in wich R is a linear or branched hydrocarbon chain of the general formula C n H( 2 n+ l ) » preferably CH 3 or C 2 H 5 .
The invention comprises of forming a salt of formula (II)
H
H
(in which R is as described earlier and HA is the chiral acid) with a chiral acid, separating the diastereomeric salts and regenerating the amide (I) in either optically active form from the separated salts.
This method gives high yields (75-80% from racemic 3-aminoquinuclidine dihydrochloride) of N-(quinuclidinyl-3)- acetamide with R- or S- absolute configuration with high optical purity (up to 99,8% e.e.).
Hydrolysis of the optically active amides gives the single enantiomers of 3-aminoquinuclidine dihydrochloride in very good yields (70-75% from racemic 3-aminoquinuclidine dihydrochloride) with unusually high optical purities (better than 99,5% e.e.).
The racemic compounds of formula (I) are obtained by acylation of racemic 3-amino-quinuclidine dihydrochloride with the respective acyl chlorides or anhydrides.
The racemic and optically active compounds of formula (I) are new compounds, as well as the compounds of formula (II).
The optically active amides of formula (I) are new compounds, as well as the compounds of formula (II).
Chiral acids which may be used to make the salt (II) include S-(+)-camphor-10-sulphonic acid, R-(-)-camphor-10 sulphonic acid and their monohydrates.
The compounds of formula (II) may be formed in any convenient way.
For example, the racemic compound of formula (I) may be dissolved in a suitable solvent, such as methanol, ethanol, isopropanol, butanol or acetone, with subsequent addition of the chiral acid dissolved in a suitable solvent, such as above. The solvent used should preferably be water-miscible.
The diastereometic mixture of salts of the formula (I) may be separated by known methods. Fractional crystallisation from an inert solvent such as methanol, ethanol, isopropanol, butanol or acetone, is preferably used.
The optically active amide of formula (I) is regenerated by treatment of the resolved salt with aqueous base (e.g. KOH, NaOH, NaHC0 3 or Na 2 C0 3 ) and extraction with a non-water- miscible solvent such as ether, chloroform or dichloromethane.
The resolved amide of the formula (I) obtained by this method may be hydrolysed with strong aqueous acid (e.g. 3-12 N HC1 or 10% sulphuric acid) or base (e.g. 10% NaOH) at high temperatures (e.g. 60-110°C) to yield optically active salt of 3-aminoquinuclidine, preferably with 6 N HC1.
The following examples illustrate the invention. Optical purity was determined by gas chromatographic analysis of the diastereomeric compounds formed with optically pure α-methoxy- phenylacetic acid chloride.
EXAMPLE 1
N-(Quinuclidinyl-3-)-acetamide.
Racemic 3-aminoquinuclidine dihydrochloride (10,25kg, 51,5 mol) was dissolved in water (20 1) . To this solution was added a solution of NaOH (2,05 kg, 51,3 mol) in water (2 1). The solution was cooled to 24°C and acetic acid anhydride (6,5 kg, 63,7 mol) was added quickly. The resulting solution was stirred for two hours at 60-28°C before addition of additional acetic acid anhydride (0,5 kg, 4,9 mol), followed by stirring for one hour.
The pH of the solution was adjusted to 13 by addition of NaOH (6,0 kg, 150 mol) and K 2 C0 3 (1,0 kg, 7,2 mol). This solution was extracted with CHC1 3 (5 x 20 1) and the solvent was removed in vacuo from the combined organic phases.
This gave 8,65 kg racemic N-(quinuclidinyl-3-)-acetamide, better than 98% pure, mp. 140-141°C.
EXAMPLE 2
N-(Quinuclidinyl-3-)-propionamide.
Racemic 3-aminoquinuclidine dihydrochloride (50g, 0,25 mol) was dissolved in water (100 ml) . To this solution was added NaOH (lOg, 0,25 mol).
The solution was cooled to room temperature and propionic anhydride (50g, 0,38 mol) was added. The resulting solution was stirred at 50-20°C for two hours. After adjustment of the pH of the solution to 13 by addition of NaOH, the solution was extracted with CHC1 3 (5 x 100 ml) . The solvent was removed under reduced pressure from the combined organic phases.
Recrystallization of the crude product gave the title compound (37g) , better than 98% pure, mp. 96-98°C.
EXAMPLE 3 S-N-(aminoquinuclidinyl-3)-acetaxαide-L-(-)-camphor-lO-sulp honate.
A solution of L-(-)-champhor-10-sulphonic acid onohydrate (3,4 kg, 13,6 mol) in acetone (17 1) was added to a solution of N-quinuclidinyl-3)-acetamide (4,8 kg, 28,6 mol) in acetone (14 1).
The mixture was cooled to 30°C with stirring, filtered and the solid washed with acetone (2 x 2,5 1). Drying of the solid yielded S-(-)-N-(aminoquinuclidinyl-3)-acetamide-L-(-)-camphor- 10-sulphonate (4,36 kg), mp. 211-214°C with an optical purity of 90%.
The crude product (5,1 kg) was dissolved in isopropanol (28 1) heated at reflux, cooled to 20°C and worked up as above, yielding the title compound (4,26 kg) . 218-220°C, [oc] 2 8 = 25,6° (c = 2, water) with an optical purity of 99,5%.
EXAMPLE 4 S-N-(aminoquinuclidinyl-3)-acetamide-L-(-)-camphor-10-sulpho nate.
A solution of L-(-)-camphor-10-sulphonic acid monohydrate (6,5 kg, 28,0 mol) in acetone (34 1) was added to a solution of N-quinuclidinyl-3)-acetamide (8,65 kg, 51,5 mol) in acetone (10 1).
The mixture was slowly cooled to 15°C with stirring. After 10 hours the precipitate was filtered and washed with acetone (2 x 3 1) and dried.
This yielded S-(-)-N-(aminoquinuclidinyl-3)-acetamide-L- (-)-camphor-lO-sulphonate (8,23 kg) mp. 218-222°C with an optical purity of 97,8%.
Recrystallization of this salt (8,23 kg) in isopropanol heated at reflux (45 1) , yielded the title compound (7,2 kg) , mp. 220-222°C, with an optical purity of 99,9%. This corresponds to 99,8% ee.
EXAMPLE 5 R-N-(aminoquinuclidinyl-3)-acetamide-D-(+)-camphor-10-sulpho nat
The mother liqueur from the first precipitation in Example 3 was evaporated to a total volume of 20 1 and added a solution of D-(+)-camphor-10-sulphonic acid (3,4 kg, 14,7 mol) in acetone (17 1) .
The mixture was worked up as in Example 3, yielding R-(+)- N-(aminoquinuclidinyl-3)-acetamide-D-(+)-camphor-10-sulphona te (4,94 kg), mp. 207-210°C with an optical purity of 80%. This crude product was dissolved in isopropanol (22,5 1) heated at reflux, cooled to 20°C with stirring and worked up as above, yielding R-(+)-N-(aminoquinuclidinyl-3)-aetamide-D-(+)-camphor- 10-sulphonate (4,05kg), mp. 215-217°C, [o.] 2 β = 24,0° (c = 2, water) with an optical purity of 99,2%.
EXAMPLE 6
S-N-(quinuclidinyl-3)-acetamide
The title compound from Example 3 (4,80 kg) was dissolved in a solution of NaOH (2,1 kg) and Na C0 3 (1,5 kg) in water (24 1).
The aqueous phase was extracted with chloroform (9 x 10 1) and the combined extracts dried over MgS04.
Removal of the solvent under reduced pressure yielded S-(-)-N-(quinuclidinyl-3)-acetamide (1,80 kg) mp. 128-131°C (with sintering), [o.] 2 β = -50,0° (c = 2, CHC1 3 ) with an optical purity of 99,5%.
EXAMPLE 7
R-N-(Quinuclidinyl-3)-acetamide
The title compound from Example 5 (4,00 kg) was dissolved in an aqueous solution of NaOH (1,76 kg) and Na 2 C0 3 (1,4 kg).
The aqueous phase was extracted with chloroform (9 x 10 1) and worked up as above, yielding R-(+)-N-(quinuclidinyl-3)- acetamide (1,41 kg), mp. 128-130°C (with sintering), [α] 2 β = +49,5° (c=2, CHCI3) with an optical purity of 99,3%.
EXAMPLE 8
S-3-Aminoquinuclidine dihydrochloride
The title compound from Example 6 (1,80 kg) was dissolved in water (2,5 1) , to this solution was added 37% HC1 (4,5 1). This mixture was heated at reflux for 3 hours while water and acetic acid (3 1) was distilled off. The residue was evaporated under reduced pressure to approx. 3 liter and treated with absolute ethanol and acetone.
The precipitated S-(-)-3-aminoquinuclidine dihydrochloride was filtered off and washed with absolute ethanol (2 x 300 ml) before drying under reduced pressure at 60°C.
This yielded the title compound (1,96 kg) mp. 310-315°C with an optical purity of 99,4% [α] 2 β = -23,5° (c=l, water) , - 40,9° (C=l, 10% NaOH).
EXAMPLE 9
R-3-Aminoquinuclidine dihydrochloride
The title compound from Example 7 (1,41 kg) was hydrolysed and worked up as in example 8, yielding R-(+)-3-aminoquinuclidine dihydrochloride (1,53 kg)mp. 311-315°C with an optical purity of 99,2%. [α] 2 β = +23,6° (c=l, water), 40,6° (c=l, 10% NaOH).
EXAMPLE 10
S-N-(aminoquinuclidinyl-3)-propionamide-L-(-)camphor-lθ- sulphonate
A solution of L-(-)-camphor-10-sulphonic acid monohydrate (10,5 g, 0,045 mol) in acetone (60 ml) was added to a solution of N-quinuclidinyl-3)-propionamide (15 g, 0,81 mol) in acetone (40 ml) .
The mixture was cooled to room temperature with stirring, filtered and the solid washed with acetone (15 ml) . Drying of the solid yielded S-(-)-N-(aminoquinuclidinyl-3)-propiona ide- L-(-)-camphor-10-sulponate (15,9 g, 0,038 mol), mp 206-209°C.
The crude product was dissolved in isopropanol (70 ml) , heated at reflux, cooled to room temperature and worked up as above, yielding the title compound (12,lg), mp 217-219°C, [ ] 0 D = -28,8° (c=2, water) with an optical purity of 99,5%.
EXAMPLE 11
R-N-(aminoquinuclidinyl-3)-propionamide-D-(+)-camphor- 10-sulphonate
To the mother liqueur from the first precipitation in Example 10 was added a solution of D-(+)-camphor-10 sulphonic acid (10,5 g, 0,045 mol). The mixture was worked up as in Example 10, yielding R-(+)-N-(aminoquinuclidinyl-3)-propionamide- D-(+)-camphor-10-sulphonate (14,0 g, 0,033 mol), mp 215-217°C.
This crude product was dissolved in refluxing isopropanol (65 ml) , cooled to room temperature with stirring and worked up as above, yielding the title compound (11,3 g) mp. 215-217°C, [α] 2 β = +22,7° (c=2, water) with an optical purity of 99,5%.
EXAMPLE 12
S-N-(quinuclidinyl-3)-propionamide
The title compound from Example 10 (10 g, 0,024 mol) was dissolved in water (50 ml) containing NaOH (4,3 g, 0,11 mol) and Na 2 C0 3 (3,1 g) . The aqueous phase was extracted with chloroform (5 x 10 ml) and the combined extracts dried over MgS0 4 .
Removal of the solvent under reduced pressure yielded S-(-)-N-(quinuclidinyl-3)-propionamide (4,7 g) , mp. 111-114°C, [ ] 2 β = -45,7° (c=2, CHC1 3 ) with an optical purity of 99,5%.
EXAMPLE 13
R-N-(Quinuclidinyl-3)-propionamide
The title compound from Example 11 (10 g) was worked up as in Example 12.
This yielded R-(+)-N-(quinuclidinyl)-3)-propionamide (4,5 g) ,mp. 111-114°C, [α] 2 β = + 49,7° (c=2, CHC1 3 ) with an optical purity of 99,5%.
EXAMPLE 14
S-3-Aminoquinuclidine dihydrochloride
The title compound from Example 12 (4,14 g) was dissolved in 6 N HCl (50 ml) and heated at 100°C for 18 hours. Water and HCl was removed under reduced pressure and the crude product treated with absolute ethanol (25 ml) , filtered and dried.
This gave S-(-)-3-aminoquinuclidine dihydrochloride (4,4 g) , mp. 310-315°C with an optical purity of 99,5%. [α] 2 β =- 39,6° (C=l, 10% NaOH).
EXAMPLE 15
R-3-Aminoquinuclidine dihydrochloride
The title compound from Example 13 (3,93 g) was treated as in Example 14, yielding R-(+)-3-aminoquinuclidine dihydrochloride (4,05 g) , mp. 310-315°C with an optical purity of 99,5%, [o:] 2 β = +40,6° (c=l, 10% NaOH).
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