HK1169983A - Optically active 3-(phthalimido)piperidine and the process for preparing the same - Google Patents

Description

Optically active 3- (phthalimido) piperidine and process for producing the same

The application is a divisional application of Chinese invention application (name of the invention: a preparation method of chiral 8- (3-amino-piperidine-1-yl) -xanthine; application date: 11/02/2005; application number: 200580037243.1).

Technical Field

The present invention relates to an improved process for the preparation of chiral 8- (3-aminopiperidin-1-yl) -xanthines, their enantiomers and their physiologically tolerable salts.

Background

8- (3-aminopiperidin-1-yl) -xanthines of the general structure

Wherein R is¹Is, for example, optionally substituted arylmethyl or optionally substituted heteroarylmethyl, R²Is, for example, alkyl, and R³For example optionally substituted benzyl or straight-chain or branched alkenyl or alkynyl groups are known from international patent applications WO 02/068420, WO 04/018468, WO 04/018467, WO2004/041820 and WO 2004/046148, in which compounds having valuable pharmacological properties are described, which include, in particular, an inhibitory effect on the activity of the enzyme dipeptidylpeptidase IV (DPP-IV). Accordingly, such compounds are suitable for use in the prevention or treatment of diseases or conditions associated with increased DPP-IV activity, or which may be prevented or alleviated by decreasing DPP-IV activity, in particular type I or type II diabetes mellitus or a decrease in glucose tolerance.

WO 04/018468 discloses a process for the preparation of 8- (3-aminopiperidin-1-yl) -xanthines by deprotection of the corresponding tert-butoxycarbonyl protected derivative of the general formula (II).

In this process, impurities are difficult to remove, which can occur in particular in industrial-scale preparations, which can be attributed to the protecting groups used. Therefore, this process is not suitable for the industrial preparation of 8- (3-aminopiperidin-1-yl) -xanthine, in particular for the preparation of pharmaceuticals, which have stringent requirements on purity. Furthermore, this process has the disadvantage of being complicated and expensive in the preparation of the enantiomerically pure (enantiomerically pure) precursor 3- (tert-butoxycarbonylamino) piperidine. However, enantiomerically pure active substances are preferred for medical applications because of the risk of side effects and the consideration of minimizing the dosage. These circumstances are disadvantageous for the suitability of the known industrial preparation of enantiomerically pure 8- (3-aminopiperidin-1-yl) -xanthines.

In view of the above-mentioned disadvantages of the known preparation processes, it is an object of the present invention to provide a process for preparing enantiomerically pure 8- (3-aminopiperidin-1-yl) -xanthines using readily available starting materials of high chemical and optical purity and without high technical costs and inconveniences. The novel process is also suitable for industrial-scale synthesis and is therefore commercially applicable.

This object is achieved by preparing chiral 8- (3-aminopiperidin-1-yl) -xanthines by the process of the present invention. In addition to the industrial feasibility of high yields, excellent chemical and optical purity are other advantages of the synthetic route of the invention.

Disclosure of Invention

According to the process of the present invention, suitable xanthine precursors (III) are enantiomerically pure or racemic (3-phthalimido)) -piperidines according to scheme 1, reacted in suitable solvents at temperatures ranging from 20 to 160 ℃, preferably from 80 to 140 ℃. The solvent used may be, for example, Tetrahydrofuran (THF), or bisAlkane, N-Dimethylformamide (DMF), Dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), or Dimethylsulfoxide (DMSO). Preferably NMP is used. The phthaloyl protecting group is subsequently removed in a manner known per se. Possible removal methods are described, for example, in "Protective Groups in Organic Synthesis", Wiley 1981, page 265 of T.W. Greene (e.g. hydrazine in ethanol).

In the above-mentioned chemical formula,

x is a leaving group which is a group selected from halogen, such as a fluorine, chlorine or bromine atom, or a sulfonate, such as phenylsulfonyloxy, p-toluenesulfonyloxy, methylsulfonyloxy or trifluoromethylsulfonyloxy.

R¹Is phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridylmethyl, pyrimidinylmethyl, quinolylmethyl, isoquinolylmethyl, quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl or phenanthridinylmethyl, where the aromatic or heteroaromatic groups are in each case substituted by R_aMono-or disubstituted, which substituents may be the same or different, and

R_ais a hydrogen, fluorine, chlorine or bromine atom or a cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy group,

or two R_aRadicals, when they are bonded to adjacent carbon atoms, may also be-O-CH₂-O-or-O-CH₂-CH₂-an-O-group,

R²is methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl and

R³is 2-buten-1-yl3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2- (trifluoromethyl) benzyl or 2-cyanobenzyl.

The process is preferably applied to these compounds, where

X is a chlorine or bromine atom,

R¹is phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridylmethyl, pyrimidinylmethyl, quinolylmethyl, isoquinolylmethyl, quinazolinylmethyl, quinoxalinylmethyl or naphthyridinylmethyl, where the aromatic or heteroaromatic groups are in each case substituted by R_aMono-or disubstituted, which substituents may be the same or different, and

R_ahydrogen, fluorine or chlorine atoms or cyano, methyl, ethyl, methoxy or ethoxy groups,

R²is methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl and

R³is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2- (trifluoromethyl) benzyl or 2-cyanobenzyl group.

The process is preferably applied to those compounds in which

X is a chlorine or bromine atom

R¹Is cyanobenzyl, (cyanopyridyl) methyl, quinolinylmethyl, (methylquinolinyl) methyl, isoquinolinylmethyl, (methylisoquinolinyl) methyl, quinazolinylmethyl, (methylquinazolinyl) methyl, quinoxalinylmethyl, (methylquinoxalinyl) methyl, (dimethylquinoxalinyl) methyl or naphthyridinylmethyl,

R²is methyl, cyclopropyl or phenyl and

R³is 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-chlorobenzyl,2-bromobenzyl or 2-cyanobenzyl,

but in particular the compounds 1- [ (4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) -xanthine, 1- [ (3-methylisoquinolin-1-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-aminopiperidin-1-yl) -xanthine and 1- [ (3-cyanopiperidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1- Yl) -xanthine, in which X is bromine.

In each case preference is given to using (R) -3- (phthalimido) piperidine as reagent. The preparation of the compounds of the formula (III) is described in the abovementioned cited documents and can be carried out according to known methods.

The present invention also provides a process for preparing optically active 3- (phthalimido) piperidines. In this process, the 3-aminopyridine is first hydrogenated according to known methods. The racemic 3-aminopiperidine thus obtained is then converted into the corresponding phthalimide by means of phthalic anhydride. The (R) enantiomer can be selectively precipitated from the racemic, crude phthalimide (IV) solution by D-tartaric acid. The (S) enantiomer of (IV) can also be obtained from the mother liquor of the salt precipitation in a simple manner by addition of L-tartaric acid without first having to remove the excess D-tartaric acid originally present in the mother liquor.

The very simple separation of the enantiomers of the compound of formula (IV) is very surprising to the person skilled in the art. The racemic base from the hydrogenation reaction does not have to be purified beforehand for this purpose. The process itself is not problematic even in industrial-scale preparations.

Furthermore, the unexpectedly complete reaction of 3-aminopiperidine with phthalic anhydride is surprising per se, since, according to the literature (for example U.S. Pat. No. 4,005,208, in particular example 27), the mixture is expected to contain, in addition to the desired product, derivatives in which the ring nitrogen atom is acylated.

The following examples illustrate the invention in more detail:

example 1:

d-tartrate salt of the R enantiomer of 3- (phthalimido) piperidine

a. Hydrogenation:

10.00kg (106.25mol) of 3-aminopyridine, 500g of technical-grade activated charcoal and 65 l of acetic acid were initially charged in a hydrogenation reactor. 50g of Nishimura catalyst (a commercial rhodium/platinum mixed catalyst) was slurried into 2.5 liters of acetic acid and flushed (flush in) with 2.5 liters of acetic acid. The hydrogenation was carried out at 50 ℃ and a hydrogen pressure of 100bar until the absorption of hydrogen ceased, and then a post-hydrogenation (post-hydrogenation) reaction was carried out at 50 ℃ for 30 minutes. The catalyst and the activated carbon are filtered off and washed with 10 l of acetic acid. The product solution is subjected to further reaction without purification.

The reaction may also be carried out under less stringent pressure.

b. Acylation

15.74kg (106.25mol) of phthalic anhydride were initially charged in the reactor. And mixed with the filtrate obtained from the hydrogenation reaction. This was flushed with 7.5 l of acetic acid and the reaction mixture was then heated to reflux, during which time about 30% of the acetic acid used distilled off within one hour. The reaction solution was cooled to 90 ℃. The product solution is subjected to further reaction without purification.

c. Optically resolving

11.16kg of D (-) -tartaric acid (74.38mol) in 50 l of absolute ethanol heated to 50 ℃ were metered into the acylation reaction solution at 90 ℃. This was flushed with 10 l of absolute ethanol and stirred at 90 ℃ for 30 minutes, during which time the product crystallized out. After cooling to 5 ℃, the product was centrifuged and washed with absolute ethanol. The product solution is subjected to further reaction without purification.

d. Recrystallization

The wet crude product was placed in a mixture of 50 liters of acetone and 90 liters of water and heated to reflux until a solution formed. Subsequently, the solution was cooled to 5 ℃ during which time the product crystallized out. The suspension is stirred for 30 minutes at 5 ℃ and the product is centrifuged and finally washed with a mixture of 20 l acetone and 10 l water. The mixture was dried at 45 ℃ under inert conditions in a drying oven.

Yield: 11.7-12.5kg (29-31% of theory)

Example 2

Synthesis of 1- [ (4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) -xanthine

a.2-chloromethyl-4-methyl-quinazoline

10.00kg (73.98mol) of 2-aminoacetophenone were initially charged and 24.5 l of 1, 4-bisAn alkane. Cooling the solution to 1At 0 ℃ with 16.72kg (458.68mol) of hydrogen chloride introduced. The reaction mixture was warmed to 22-25 ℃. At which temperature hydrogen chloride is reintroduced. About half the total amount introduced, the mixture was cooled to-10 ℃ and introduction was continued. Subsequently, the resulting suspension was left at-10 ℃ overnight. 2.5 l of 1, 4-bis (chloroacetonitrile) (6.70 kg, 88.78mol) are added at-10 ℃ in one hourAnd (3) an alkane solution. 2 liters of 1, 4-bis are flushed into a raw material vessel (feed vessel)An alkane. Thereafter, the contents of the reactor were warmed to 6 ℃ and stirred for an additional 2 hours.

A further reactor was initially charged with a mixture of 122 l of water and 62.04kg (775.31mol) of sodium hydroxide solution (50%) and cooled to 6 ℃. The reaction mixture of the first reactor was added in portions. The temperature of the interior does not exceed 11 ℃. Subsequently, the first reactor was first run through 6 liters of 1, 4-bisThe alkane was washed, then with 6 liters of water. The resulting suspension was stirred at 5 ℃ for a further 30 minutes. The product was centrifuged, washed with 41 l of water and dried in a drying cabinet under inert conditions at 35 ℃.

Yield: 10.5-12.1kg (74-85% of theory)

1- [ (4-Methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine

10.00kg (33.66mol) of 3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine, 7.13kg (37.02mol) of 2-chloromethyl-4-methylquinazoline, 3.92kg (37.02mol) of anhydrous sodium carbonate and 30 l of N-methyl-2-pyrrolidone were initially charged in a reactor. The reactor contents were heated to 140 ℃ and stirred at 140 ℃ for 2 hours. After the reaction was complete, the reaction mixture was cooled to 80 ℃ and diluted with 60 liters of 96% ethanol, followed by 55 liters of water at 70 ℃. At 60 ℃, 4.04kg (67.32mol) of acetic acid are metered in and 5 l of water are flushed in. The resulting suspension was stirred at 60 ℃ for 30 minutes, then cooled to 23 ℃ and stirred for a further 30 minutes. The product was then centrifuged and washed first with a mixture of 20 liters of 96% ethanol and 20 liters of water and then with a mixture of 40 liters of 96% ethanol and 40 liters of water. Drying at 45 ℃ under inert conditions (under inertization) in a drying cabinet.

Yield: 11.6-12.6kg (76-83% of theory)

1- [ (4-Methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -phthalimidopiperidin-1-yl) -xanthine

10.00kg (22.06mol) of 1- [ (4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine, 12.59kg (33.09mol) of 3- (phthalimido) piperidine D-tartrate and 17.5 l of N-methyl-2-pyrrolidone were initially charged in the reactor. The reactor contents were heated to 140 ℃. After this temperature had been reached, 11.41kg (88.24mol) of diisopropylethylamine were metered in over the course of 20 minutes. 2.5 l of N-methyl-2-pyrrolidone were flushed into the feed vessel and the reaction mixture was subsequently stirred at 140 ℃ for 2 hours. After the reaction was complete, the reaction mixture was cooled to 60 ℃ and diluted with 80 liters of methanol. The resulting suspension was stirred at 50 ℃ for 30 minutes, then cooled to 23 ℃ and stirred for another 30 minutes. The product was subsequently centrifuged and washed 3 times with 20 l of methanol each. Drying at 45 ℃ under inert conditions in a drying cabinet.

Yield: 12.0-12.5kg (90-94% of theory)

1- [ (4-Methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) -xanthine

1800kg (3mol) of 1- [ (4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -phthalimidopiperidin-1-yl) -xanthine were heated to 80-85 ℃ in 18 l of toluene. Subsequently, 1.815 l (30mol) of ethanolamine was added to the suspension at 75-80 ℃. The mixture was stirred at 80-85 ℃ for 2 hours to complete the reaction, during which time the solid went into solution. Followed by phase separation. The ethanolamine layer was washed twice with warm toluene (4 liters each). The combined toluene layers were washed twice each time with 8 liters of water at 75-80 ℃. 22 l of toluene were distilled off from the toluene layer under reduced pressure. 4 l of tert-butyl methyl ether are metered into the resulting suspension at 40-50 ℃ and subsequently cooled to 0-5 ℃. The product is isolated by filtration, washed with tert-butyl methyl ether and dried under vacuum (suction dry). The wet crude material was then heated to reflux with 5 times the amount of absolute ethanol and the hot solution was purified by filtration over activated carbon. After cooling the filtrate to 20 ℃, crystallization started and it was diluted to two volumes with tert-butyl methyl ether. The suspension is cooled to 2 ℃ and stirred for a further 2 hours, filtered off with suction and dried at 45 ℃ in a vacuum drying cabinet.

Yield: 1174g (83.2% of theory)

Another method of step d:

1400kg (2.32mol) of 1- [ (4-methylquinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -phthalimidopiperidin-1-yl) -xanthine were initially taken in 4.9 l of tetrahydrofuran and subsequently heated to 55-65 ℃. Thereafter, 350ml of water and 1433g (2.32mol) of ethanolamine are added to the suspension. The mixture was stirred at 60-63 ℃ for an additional 3 hours to complete the reaction. Thereafter, 619ml of a 45% sodium hydroxide solution and 3.85 l of water were added, and the mixture was stirred at 55-65 ℃ for 30 minutes, then 5.6 l of toluene was added to the reaction mixture, and the mixture was stirred for 15 minutes, after which phase separation was carried out. The organic layer was washed with 2.8 liters of water at 55-65 ℃ and then separated. 4.2 l were distilled off from the organic layer under reduced pressure. Thereafter, 1.4 liters of methylcyclohexane were added at 65-75 ℃ during which the product crystallized. The suspension is stirred at 15-25 ℃ for 8-16 hours and then cooled to 0-5 ℃. The product is isolated by filtration, washed with 4.2 l of methylcyclohexane, dried under vacuum and dried at 35 ℃ under reduced pressure. The dried crude material (991g) was then heated under reflux with 5 times the amount of methanol, activated carbon was added and the mixture was filtered. The methanol was distilled to reduce the filtrate volume to 1.5 liters. The filtrate was cooled to 45-55 ℃ and then diluted with tert-butyl methyl ether to four volumes. The suspension is cooled to 0-5 ℃, stirred for 2 hours, filtered with suction, washed with tert-butyl methyl ether and dried in a vacuum drying oven at 35 ℃.

Yield: 899g (81.9% of theory)

Example 3

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine

a.3-cyano-2- (chloromethyl) -pyridine

165.5g (0.98mol) of 2-hydroxymethyl-3-pyridinecarboxamide (pyrimethanamide) and 270ml of phosphorus oxychloride (phosphoric oxide) were heated together at 90 to 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature and then about 800ml of water was added dropwise at 50-60 ℃. After hydrolysis of the phosphorus oxychloride, it is neutralized with sodium hydroxide solution with cooling, during which the product precipitates. It is filtered, washed with 300ml of water and subsequently dried at 35-40 ℃.

Yield: 122.6g (82% of theory)

The other method of the step a comprises the following steps: 3-cyano-2- (chloromethyl) pyridine

20.0g (131.45mmol) of 2-hydroxymethyl-3-pyridinecarboxamide are suspended in 110ml of acetonitrile and heated to 78 ℃. 60.65g (395.52mmol) of phosphorus oxychloride were metered into the mixture over 15 minutes and the mixture was heated at 81 ℃ for 2 hours. After cooling at 22 ℃ the reaction mixture is stirred in 200ml of water at 40 ℃. After addition of 100ml of toluene, the mixture was neutralized with sodium hydroxide solution under cooling. After phase separation, the organic layer was washed with 100ml of water. The organic layer was removed and the solvent was evaporated under reduced pressure to give an initially produced oily residue which was allowed to stand for crystallization.

Yield: 16.66g (83% of theory)

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine

202g (0.68mol) of 3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine, 188.5g (1.36mol) of anhydrous potassium carbonate and 1.68 l of N-methyl-2-pyrrolidone (pyrollidone) were initially charged in a reactor and heated to 70 ℃. Subsequently, 119g (0.75mol) of 2-chloromethyl-3-cyanopyridine in 240ml of N-methyl-2-pyrrolidone (NMP) solution were added dropwise. The reactor contents were stirred at 70 ℃ for 19 hours. After the reaction was complete, 2.8 liters of water were added to the reaction mixture and cooled to 25 ℃. The product is filtered off, washed with 2 l of water and dried in a drying cabinet at 70 ℃ under inert conditions.

Yield: 257.5g (91% of theory)

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -phthalimidopiperidin-1-yl) -xanthine

230g (0.557mol) of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8-bromoxanthine, 318g (0.835mol) of 3- (phthalimido) piperidine D-tartrate and 1.15 l of N-methyl-2-pyrrolidone were initially charged in the reactor. The reactor contents were heated to 140 ℃. After this temperature had been reached, 478ml (2.78mol) of diisopropylethylamine were metered in over 20 minutes, and the reaction mixture was subsequently stirred at 140 ℃ for 2 hours. After this time, the reaction mixture was cooled to 75 ℃ and diluted with 720ml of methanol, after which 2.7 l of water were added at 68-60 ℃ and the mixture was cooled to 25 ℃. The product was filtered off and washed with 2 l of water. Drying was carried out at 70 ℃ under inert conditions in a drying cabinet.

The crude product obtained is then stirred by boiling in 1 l of methanol, filtered hot, rinsed with 200ml of methanol and subsequently dried under inert conditions at 70 ℃.

Yield: 275g (88% of theory)

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -aminopiperidin-1-yl) -xanthine

412.5g (0.733mol) of 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -phthalimidopiperidin-1-yl) -xanthine were heated to 80 ℃ in 4125ml of toluene. 445ml of ethanolamine (7.33mol) were subsequently added to the suspension at 75-80 ℃. The mixture was stirred at 80-85 ℃ for an additional 2 hours to complete the reaction, during which time the solids went into solution. After that, phase separation was performed. The ethanolamine phase is extracted twice with warm toluene (1 liter each time). The combined toluene phases were washed twice with 2 l water each time at 75-80 ℃. The toluene phase was dried over sodium sulfate, filtered and then distilled under reduced pressure to reduce the volume to about 430 ml. 1 l of tert-butyl methyl ether are then metered in at 50-55 ℃ and the mixture is cooled to 0-5 ℃. The product was isolated by filtration, washed with tert-butyl methyl ether and dried in a drying cabinet at 60 ℃.

Yield: 273g (86% of theory)

Melting point: 188 +/-3 DEG C

In analogy to examples 2 and 3, 1- [ (3-methylisoquinolin-1-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine was also prepared.

Claims (8)

1. (R) -3- (phthalimido) piperidine.
2. (S) -3- (phthalimido) piperidine.
3. (R) -3- (phthalimido) piperidine D-tartrate.
4. (S) -3- (phthalimido) piperidine L-tartrate.
5. 5. A process for the preparation of (R) -3- (phthalimido) piperidine comprising the synthetic steps of:

   a) reacting racemic-3-aminopiperidine with phthalic anhydride in a suitable solvent, and

   b) (R) -3- (phthalimido) piperidine is isolated from the resulting solution of rac-3- (phthalimido) piperidine by adding D-tartaric acid and isolating the precipitated tartrate salt.
6. 6. A process for the preparation of (S) -3- (phthalimido) piperidine comprising the synthetic steps of:

   a) reacting racemic-3-aminopiperidine with phthalic anhydride in a suitable solvent, and

   b) (S) -3- (phthalimido) piperidine is isolated from the resulting solution of rac-3- (phthalimido) piperidine by addition of L-tartaric acid and separation of the precipitated tartrate salt.
7. 7. A process for the preparation of (S) -3- (phthalimido) piperidine comprising the synthetic steps of:

   a) reacting racemic-3-aminopiperidine with phthalic anhydride in a suitable solvent, and

   b) separating the (R) -3- (phthalimido) piperidine from the solution of the rac-3- (phthalimido) piperidine obtained by adding D-tartaric acid and separating the precipitated tartrate salt, and

   c) l-tartaric acid was added to the mother liquor obtained from the first salt precipitation and the precipitated (S) -3- (phthalimido) piperidine tartrate salt was isolated.
8. 8. The process according to any one of claims 5 to 7, wherein the solvent used in step b) is ethanol.