PROCESS FOR THE PREPARATION OF 4-(FLUOROPHENYL)PIPERIDINE ESTERS
The present invention relates to novel piperidine compounds which are valuable intermediates for preparing pharmaceutically active compounds, and processes thereto.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US 3,912,743 and US 4,007,196. An especially important compound among those disclosed is paroxetine, the (-) trans isomer of 4-(4'-fluorophenyl)-3- (3',4'-methylene dioxyphenoxymethyl)piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
Piperidine compounds of structure (1) and (2) are described in US 4,007,196, EP 0219934, and Acta Chemica Scandinavica (1996) volume 50 page 164 as chemical intermediates useful for the manufacture of paroxetine (3).
Thus in the process described in US-A-4007196, arecoline base is liberated from the hydrobromide salt and reacted with the Grignard reagent 4-fluorophenyl magnesium bromide to give a piperidine ester of structure (1). This piperidine ester is converted to a piperidine carbinol of structure (2), which is coupled with sesamol, then deprotected, to give paroxetine (3).
Paroxetine is the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine. The above described processes produce compounds of structure (1) as a mixture of enantiomers, and conversion of compounds of structure (1) to useful pharmaceuticals will normally require a resolution stage.
Particularly useful compounds of structure (1) and (2) are therefore those where the stereo- configuration is (-) trans-, that is a compounds of structure (A) and (B), as this configuration corresponds to that of paroxetine.
(A) (B)
There are two possible approaches to the preparation of the (-) trans carbinol, compound (B). One approach is to reduce compound (1) to compound (2), and then carry out a resolution step to give compound (B). Such an approach is described in Examples 5 and 8 of EP 0223, 334, where a racemic carbinol of structure (2) is resolved using either nitrotartanilic acid or di-p-toluoyl tartaric acid.
The second approach is to first produce the (-) trans ester compound (A), and subsequently reduce this to compound (B). The second approach is clearly advantageous, as only half the quantity of hydride reducing agent is required, representing a significant cost saving.
This application provides processes which enable the second approach to be carried out on a manufacturing scale. This application further provides novel salts of piperidine esters which are useful in the isolation, purification and resolution of such piperidine esters.
In the process described in US 4,007,196 and Acta Chemica Scandinavica (1996) volume 50 page 164, arecoline is reacted with 4-fluorophenylmagnesium bromide to give a compound of structure (1) as a mixture of racemic cis- and trans isomers, which is converted to a racemic trans-compound of structure (1) by reaction with sodium methoxide in an organic solvent at elevated temperature.
In the process described in EP 0219934, reduction of a quaternary pyridinium salt produces a compound of structure (1) exclusively in the racemic cis- configuration. This is similarly epimerised to a racemic trans-compound of structure (1) by reaction with sodium methoxide in an organic solvent at elevated temperature.
An outline method for the chemical resolution of trans l-methyl-3-carbornethoxy-4-(4'- fluorophenyl) piperidine using unspecified optical forms of mandelic acid or dibenzoyl tartaric acid has been described in the literature in the form of a flowchart [Acta Chemica Scandinavica (1996) volume 50 page 164], but no details of the conditions are given. The same flowchart outlines the reduction of the (-) trans ester (A) to the (-) trans carbinol (B).
We have made numerous attempts carry out this resolution procedure but have been unable to obtain any crystallise salts using either mandelic acid or dibenzoyl tartaric acid in a wide range of organic solvents. In addition, no chemical or physical properties for the individual (+) and (-) optical isomers of trans l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine or analogous trans compounds of structure (4) below, in which R and R' are independently an alkyl, aryl, or arylalkyl group, most suitably lower alkyl, have been reported, either as salts or in the free base form.
(4)
We therefore conclude that no workable process for obtaining (-) trans l-methyl-3- carbomethoxy-4-(4'-fluorophenyl) piperidine (A) or analogous resolved trans compounds of structure (4) is available in the prior art.
In addition, no description or preparation of the individual (+) and (-) isomers of cis 1- methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine or analogous resolved cis compounds corresponding to structure (4) has previously been described.
In a first aspect, the present invention is based on the discovery that salts of the cis ester of structure (1) with chiral acids may be prepared and used to generate novel (+) cis and (-) cis isomers of compound (1).
In addition we have surprisingly found that the desired (-) trans ester of structure (A) can be obtained from the racemic cis ester by a novel procedure which comprises resolution of the racemic cis ester by the formation of a salt with a chiral acid to give the (+) cis form, followed by an epimerisation reaction with a strong base. In this process inversion of configuration occurs, providing the (-) trans ester in good yield and high optical purity, suitable for reduction to the (-) trans form of the carbinol, compound (B).
Accordingly the first aspect of the present invention provides a process for the preparation of the (-) trans ester of structure (4), the process comprising resolution of the corresponding racemic cis ester by the formation of a salt with a chiral acid to give the (+) cis ester, followed by epimerisation of the (+) cis ester with a strong base.
In structure (4), R' may be any group that is easily removable, for example by hydrolysis or reduction, for example using lithium aluminium hydride, to generate the corresponding carbinol. Suitable groups include methyl and ethyl. Similarly R may be any N-protecting group that is easily removable. Suitable groups include methyl and benzyl.
The process of the first aspect of this invention is particularly convenient as the racemic cis ester starting material is a crystalline solid which can be readily isolated. The racemic cis ester may be prepared as in EP 0219934 mentioned above. Alternatively a mixture of racemic cis and trans esters may be prepared as in US 4,007,196 and Acta Chemica Scandinavica (1996) volume 50 page 164 mentioned above, and the racemic cis ester isolated as a crystalline salt. Surprisingly we have found that treatment of the racemic
cis/trans mixture with a chiral acid results initially in crystallisation of a racemic cis salt, which on recrystallisation yields predominantly (+) cis salt.
Accordingly in a typical procedure, the racemic cis ester is obtained by treating a racemic cis/trans mixture of the ester with a chiral acid to obtain a crystalline salt of the racemic cis ester and the chiral acid, and recrystallising the salt to obtain a salt of the (+) cis ester, which is treated with a base to recover the (+) cis ester for epimerisation.
Crystalline chiral acid salts of the racemic cis-ester of structures (4) and (1), and of the (+) and (-) isomers, are believed to be novel.
The racemic cis-ester may be liberated from the racemic cis-ester salt by treatment in solution with a base, such as aqueous sodium hydroxide, and isolated. Treatment of a solution of the racemic cis-ester with appropriate chiral acids allows the formation of- crystalline salts of the individual (+) isomers (for example with L(-) dibenzoyl tartaric acid or (+)-di-p-toluoyl-D-tartaric acid) and (-) isomers (for example with (-)-di-p-toluoyl-L- tartaric acid).
The (+) and (-) isomers of the cis-compound of structures (4) and (1) liberated from the chiral salts by treatment with a base are also believed to be novel.
The (-) cis esters of structures (4) and (1) may be epimerised with a strong base to obtain the corresponding (+) trans esters, which are also believed to be novel.
In a second aspect, the present invention is based on the surprising discovery that, despite the failure of the racemic trans ester to form salts directly with chiral acids, a limited number of non-chiral acids, for example citric acid, oxalic acid, phosphoric acid hydrobromic acid and hydroiodic acid can be used to form crystalline salts with the crude racemic trans ester.
Such crystalline salts are useful and convenient intermediates for the large scale isolation and purification of the racemic trans ester, the free base of which is an oil and otherwise
difficult to isolate in pure form. The purified racemic trans ester of structure (4) may be used to prepare the racemic trans carbinol of structure (5) which may be resolved and converted to paroxetine by known methods.
Accordingly the second aspect of the present invention provides a process for the preparation of a crystalline salt of a racemic trans compound of structure (4) which comprises contacting a solution of racemic trans compound of structure (4) with a suitable acidic component, isolating the crystalline product and optionally recrystallising the product.
We have found that citric acid, oxalic acid phosphoric acid hydrobromic acid and hydroiodic acid are especially suitable for the formation of such salts, particularly for compounds of structure (1) i.e. structure (4) where R is methyl.
Crystalline salts of the racemic trans compound of structures (4) and (1) are believed to be novel.
Similarly formed salts of the racemic cis esters with non-chiral acids are also believed to be novel.
Preferably the acidic component or a solution thereof is added to a solvent extract of the racemic trans compound of structure (4) from the previous reaction step. Suitable solvents include toluene, optionally with an additional solvent such as acetone.
The racemic trans compound of structure (4) may be liberated in purified form from the crystalline salt by conventional means, for example by treatment with an inorganic base followed by extraction with a solvent such as toluene. In a particularly useful aspect of the invention the extract of the purified racemic trans compound is used directly in the reduction step to generate a racemic trans carbinol of structure (5). This reduction may be carried out with a reducing agent such as lithium aluminium hydride, optionally employing an additional solvent such as tetrahydrofuran.
In a third aspect, the present invention is based on the surprising discovery that the pure (-) trans ester of structure (4) or (1) produced in accordance with the first aspect of this invention may be used to form crystalline salts with non-chiral and chiral acids. The chiral acid salts may be used as seed crystals to enable the otherwise extremely difficult resolution of racemic trans ester with chiral acids to be carried out, particularly when the racemic trans ester has first been purified using the second aspect of this invention.
We have surprisingly found that although a crystalline salt could not be generated by reaction of the pre-formed (-) trans ester of structure (1) with dibenzoyl tartaric acid, the acid allegedly employed in the prior art, it was possible to form a crystalline salt between the pre-formed (-) trans ester of structure (1) and di-toluoyl tartaric acid. In addition , we have been able to carry out a resolution of the racemic trans ester of structure (1) using the aforementioned di-toluoyl tartaric acid salt as seeds.
Accordingly the third aspect of the present invention provides a process for the preparation of the (-) trans ester of structure (4) which comprises forming a solution of the product of the process of the second aspect of this invention and a chiral acid, and seeding the solution with a crystalline salt formed from the (-) trans product of the process of the first aspect of this invention and the same chiral acid.
Similarly, a crystalline salt formed directly between a (+) trans ester isomer (obtained by epimerisation of a (-) cis ester isomer as described previously) and a chiral acid may be used as seed to obtain a crystalline (+) ester salt from a solution of the racemic ester salt.
Crystalline salts of the (-) trans and (+) trans compound of structures (4) and (1) are believed to be novel.
Compounds of structure (4) may be converted to the active compound paroxetine using conventional procedures disclosed in US-A-3912743 or US-A-4007196, whereby the piperidine ester of structure (4) is reduced to a piperidine carbinol of structure (5), which is coupled with sesamol, then deprotected, to give paroxetine (3).
The present invention includes within its scope the compound paroxetine and its pharmaceutically acceptable salts, particularly paroxetine hydrochloride, especially as an anhydrate or the hemihydrate, and paroxetine methanesulphonate, when obtained via any aspect of this invention, and any novel intermediates resulting from the described procedures.
Paroxetine free base may be converted to paroxetine methanesulphonate by treatment with methanesulphonic acid or a labile derivative thereof, for example a soluble salt such as arnmonium methanesulphonate. Paroxetine hydrochloride may be prepared by treatment of paroxetine free base with a source of hydrogen chloride, for example gaseous hydrogen chloride, or a solution thereof, or aqueous hydrochloric acid.
Paroxetine and its salts obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO96/24595, either as solid formulations or as solutions for oral or parenteral use.
Therapeutic uses of paroxetine, especially paroxetine hydrochloride or methanesulphonate, obtained using this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders".
Pharmaceutical compositions using active compounds prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
The composition is usually presented as a unit dose composition containing from 1 to
200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release.
The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilised in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
Accordingly, the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of one or more of the Disorders comprising paroxetine or a pharmaceutically acceptable salt such as the mesylate or hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier; the use of paroxetine or a pharmaceutically acceptable salt such as the mesylate or hydrochloride obtained using the process of this invention to manufacture a medicament for the treatment or prophylaxis of one or more of the Disorders; and a method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or a pharmaceutically acceptable salt such as the
mesylate or hydrochloride obtained using the process of this invention to a person suffering from one or more of the Disorders.
This invention is illustrated by the following Examples.
Analytical Procedures
The stereo configuration of piperidine esters of structure (1) may be determined by conventional means, for example by NMR. The cis ester of structure (1) gives an NMR signal in deuterochloroform at ca δ 3.51 ppm for the methyl protons of the ester group, whereas the trans ester of structure (1) has a signal at ca δ 3.44.
The optical purity of piperidine esters of structure (1) may be assessed by measurement of optical rotation, or by chiral HPLC or preferably by chiral capillary electrophoresis. A review entitled "Separation of optically active pharmaceuticals using capillary electrophoresis" by T.J. Ward, and K. D. Ward has been published in Chem. Anal. (N. Y.) (1997), volume 142 pages 317-344.
Example 1 Preparation of trans-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine oxalate
Crude trans- 1-methy 1-3 -carbomethoxy-4-(4'-fiuorophenyl)piperidine (2.60g) was added to a solution of oxalic acid (0.95g) in ethanol (30 ml) and stirred to give a clear solution. The solution was diluted with hexane (30 ml) and diethyl ether (60 ml), stirred for 1 hour at ambient temperature then stored at 5 °C for a further 1 hour. The resulting crystals were collected by filtration, washed with diethyl ether (20 ml) and dried.
Yield 1.98g.
The IR spectrum (attenuated total reflectance) showed bands at inter alia 3038, 2951, 1734, 1601, 1512, 1436, 1330, 1225, 1173, 1161, 1140, 1000, 959, 797, 754, 711 cm-1.
X-ray diffractogram, major peaks (CuK.2α):
Example 2
Regeneration of trans-l-methyI-3-carbomethoxy-4-(4'-fluorophenyl) piperidine from the oxalate salt
Trans- 1-methy 1-3- carbomethoxy-4-(4'-fluorophenyl)piperidine oxalate (1.0g) was suspended in ethyl acetate (20 ml) and 10%w/v aqueous sodium hydroxide (10 ml) was added to dissolve the solid. The layers were separated and the aqueous layer was extracted again with ethyl acetate (20 ml). The combined organic layers were dried over magnesium sulphate, and the solvent removed by evaporation to give pure trans -l-methyl-3- carbomethoxy-4-(4'-fluorophenyl)piperidine as an oil.
Yield 0.59 g.
Example 3 Preparation of trans-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine hydrobromide.
48% aqueous hydrobromic acid (0.36 g) was added to a solution of trans- l-methyl-3- carbomethoxy-4-(4'-fiuorophenyl)-piperidine (0.50 g) in ethanol (15 ml) and mixture stirred for 2 hours. The resulting suspension was stored at 5°C for 72 hours then the crystals were filtered and dried in vacuum.
Yield 0.30 g.
The IR spectrum (attenuated total reflectance) showed bands at inter alia 2949, 2675, 1735, 1512, 1433, 1331, 1209, 1168, 1143, 961, 831, 796 cm"1.
The X-ray powder diffractogram (CuK2α) showed the following significant peaks
Example 4 Preparation of hydroiodic acid salt of trans-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl)piperidine
A solution of 55% hydroiodic acid (0.19 g) in ethanol (5 ml) was mixed with a solution of trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (0.20 g) in ethanol (5 ml) and the clear solution was stirred well. The solvent was removed by evaporation to give the product as a yellow solid, whiich was recrystallised from ethyl acetate.
The IR spectrum (attenuated total reflectance) showed bands at inter alia 2932, 2701, 1735, 1511, 1329, 1226, 1163, 959 and 794 cm"1.
The X-ray powder diffractogram (CuK2α) showed the following significant peaks
Example 5 Preparation of the citric acid salt of trans-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl)piperidine
A solution of citric acid (0.20 g) in acetone (5 ml) was added to trans- l-methyl-3- carbomethoxy-4-(4'-fluorophenyl)piperidine (0.25 g) and stirred well to give a clear solution. The solution was concentrated to approximately 3 ml by evaporation under reduced pressure, whereupon crystals began to form. The crystalline salt was collected by filtration, washed with acetone (5 ml) and dried under vacuum
Yield 0.30 g.
Analysis by NMR showed that the molar ratio of citric acid to trans- l-methyl-3- carbomethoxy-4-(4'-fluorophenyl)piperidine was 1 :1.
The IR spectrum (attenuated total reflectance) showed bands inter alia at 1727, 1583, 1512, 1436, 1330, 1208, 1174, 1139, 1084r 963, 831, 796, 773, 721 and 664 cm"1.
The X-ray powder diffractogram (CuK2α) showed the following significant peaks
Example 6
Preparation of the phosphate salt of trans-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl)piperidine.
A 10% v/v solution of orthophosphoric acid in propan-2-ol (0.68 ml) was added to a solution of trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (0.25 g) in propan-2-ol (5 ml) to give a white oil. Crystallisation was induced by stirring with additional propan-2-ol (10 ml) and n-hexane (15 ml) for 1 hour at ambient temperature. The suspension was stored at 4°C overnight, then the crystalline salt was collected by filtration and dried under vacuum.
Yield 0.23g.
Analysis by ion chromatography showed that the ratio of phosphoric acid to trans- 1- methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine was approximately 1 :1.
The IR spectrum (attenuated total reflectance) showed bands inter alia at 1726, 1603, 1513, 1437, 1331, 1256, 1221, 1169, 1101, 1049, 888, 847, 796, 771 and 755 cm-'.
The X-ray powder diffractogram (CuK2α) showed the following significant peaks:
Example 7
Resolution of cis l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine using L(-) dibenzoyl tartaric acid
i) Cis/trans l-mefhyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (2.18 g), prepared by the method of Example 1 of US 4,007,196, was dissolved in acetone (40 ml) and treated with L(-)-dibenzoyl tartaric acid (4.0 g). The mixture was allowed to stand at 5°C for several days, then the crystals were collected, washed with acetone and dried in vacuum.
Yield 2.73 g
NMR analysis confirmed that only the salt of the cis-form had crystallised. Analysis by chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was 1 :1.
ii) 1.0 g of the above salt was recrystallised by warming in methanol (10 ml) and storing the solution at 5 C for 18 hours. The resulting crystals were collected by filtration, washed with methanol and dried in vacuum. Chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was 91 :9.
(+) cis l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine L(-)-dibenzoyl tartrate may aso be prepared directly from racemic cis l-methyl-3-carbomethoxy-4-(4'- fluorophenyl)piperidine by heating with L(-)-dibenzoyl tartaric acid in acetonitrile and allowing the mixture to cool.
Example 8
Preparation of (+)cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine (+)-di- p-toluoyl-D-tartrate from crude cis/trans ester.
i) Crude cis/trans- l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (20 g) was dissolved in acetone (100 ml) and mixed with a solution of (+)-di-p-toluoyl-D -tartaric acid monohydrate (33 g) in acetone (50 ml). The flask was sealed and stored at 5°C for 18 hours. The crystals were collected by filtration, washed with acetone (25 ml) and dried under vacuum.
Yield 28.3 lg
Chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was approximately 1 : 1
ii) Cis- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine (+)-di-p-toluoyl- D- tartrate (25 g) was dissolved in boiling methanol (50 ml) then allowed to cool to room temperature. The flask was sealed and stored at 5°C for 4 days during which time crystals separated. These were collected by filtration, washed with acetone (10 ml) and dried under vacuum.
Yield 7.36g
Chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was approximately 75:25
Example 9
Preparation of (+)cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyι) .piperidine
Recrystallised (+) cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (+)-di-p- toluoyl-D-tartrate (7 g) was suspended in a mixture of ethyl acetate (120 ml) and water (60 ml), and 10% w/v aqueous sodium hydroxide (10 ml) was added to dissolve the salt. The layers were separated and the aqueous phase was extracted again with ethyl acetate (60 ml). The combined ethyl acetate layers were dried over magnesium sulphate, and the solvent evaporated under reduced pressure to give (+) cis-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl) piperidine as a crystalline solid.
Yield 2.18g.
[α]26 D + 40° (c = 1, methanol)
(+) cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine be similarly liberated from the recrystallised L (-)-dibenzoyl tartrate salt as prepared in Example 7.
Example 10 Preparation of (+)cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl) piperidine (+)-di- p-toluoyl-D-tartrate from the cis ester.
i) Cis-l-methyl-3-carbomethoxy-4-(4,-fluorophenyl)piperidine (1.0 g) prepared by the method of Example 2 of EP 0219934, was dissolved in acetone (5 ml) and mixed with a solution of (+)-di-p-toluoyl-D- tartaric acid monohydrate (1.6g) in acetone (5 ml).
Crystals separated on stirring and the suspension was left to stand for several hours. The crystals were collected by filtration, washed with acetone (5 ml) and dried under vacuum.
Yield 2.11g.
Chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was approximately 1 :1
ii) Cis- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine (+)_-di-p-toluoyl-D- tartrate (1.0 g) was dissolved in hot methanol (5 ml) then allowed to cool. The flask was stored at 5°C for 18 hours during which time crystals separated. The crystals were collected, washed with methanol (5 ml) and dried under vacuum
Chiral capillary electrophoresis showed that the ratio of (+) cis to (-) cis was approximately 90:10.
Example 11
Preparation of (-)cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (-)-di-p-toluoyl-L-tartrate from the cis ester.
i) Cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine ( 1.0g) was dissolved in acetone (5 ml) and mixed with a solution of L(-)-di-p-toluoyl tartaric acid (1.52g) in acetone (5 ml). Crystals separated on stirring and the suspension was left to stand for several hours. The crystals were collected by filtration, washed with acetone (5 ml) and dried under vacuum.
Yield 1.79g.
ii) Cis- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine (-)-di-p-toluoyl-L- tartrate (1.0 g) was dissolved in hot methanol (5 ml) then allowed to cool. The flask was sealed and stored at 5°C for 7 hours during which time crystals separated. The crystals were collected by filtration, washed with methanol (5 ml) and dried under vacuum.
Yield 0.2 lg
Chiral capillary electrophoresis showed that the ratio of (-) cis to (+) cis was approximately 89 : 11
Example 12
Preparation of (-)cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine
(-) cis- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine is regenerated from the (-) cis- 1 -methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine (-)-di-p-toluoyl-L-tartrate produced in Example 11 (ii) using the procedure of Example 9.
(-) cis- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine may also be prepared by employing D(+)-dibenzoyl tartaric acid in place of L(-)-dibenzoyl tartaric in the procedure described in Example 7, to give (-) cis-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl)piperidine D(+)-dibenzoyl tartrate, and liberating the product from this salt using the procedure of Example 9.
The product has an optical rotation, [α]26 D (c = 1, methanol), of about - 40°
Example 13
Preparation of (-) trans -l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine
(+) cis-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine, as prepared in Example 9, (0.35g), is dissolved in dry toluene (10 ml) and treated with sodium methoxide (0.15g). The mixture is heated to reflux under nitrogen for 2 hours, then allowed to cool to ambient temperature. The solution is washed with water (10 ml) followed by saturated aqueous sodium chloride (10 ml) and the toluene is evaporated under reduced pressure to give (-)- trans- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine as an oil. A yield of about 0.30g is obtained, having the following properties:
N.M.R. δ (CDC13) ~ 7.15 (m, 2H), 6.95 (q, 2H), 3.44 (s, 3H, methyl ester), 3.10 (m, 1H), 2.88 (m, 2H), 2.75 (m, 1H), 2.18 (m, 2H), 1.80 (m, 2H).
Optical rotation [α]26 D ca. - 44 ° (c =1, methanol)
Example 14 Preparation of (+) trans -l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine
(-) cis- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine, as prepared in Example 12, (0.35g), is dissolved in dry toluene (10 ml) and treated with sodium methoxide (0.15g). The mixture is heated to reflux under nitrogen for 2 hours, then allowed to cool to ambient temperature. The solution is washed with water (10 ml) followed by saturated aqueous sodium chloride (10 ml) and the toluene is evaporated under reduced pressure to give (+)-trans-l -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperi dine as an oil. A yield of about 0.30g is obtained, having the following properties:
N.M.R. δ (CDC13) ~ 7.15 (m, 2H), 6.95 (q, 2H), 3.44 (s, 3H, methyl ester), 3.10 (m, IH), 2.88 (m, 2H), 2.75 (m, IH), 2.18 (m, 2H), 1.80 (m, 2H).
Optical rotation [α]26 D ca. + 44 ° (c =l, methanol)
Example 15
Preparation of L(-)-di-p-toluoyl tartaric acid salt of (-)-trans-l-methyI-3- carbomethoxy-4-(4'-fluorophenyl)piperidine.
L(-)-di-p-toluoyl tartaric acid (0.154 g) was added to (-)-trans-l -methyl-3 -carbomethoxy- 4-(4'-fluorophenyl)piperidine (0.10 g) and the mixture was stirred well in acetone (5 ml). The solvent was removed by evaporation to give an oil. Ethanol (5 ml) and water (10 ml) were added and crystallisation was induced by stirring. The crystals were collected by filtration dried under vacuum
Yield 0.14 g.
NMR indicated that a 1 : 1 salt had been formed
The IR spectrum showed bands inter alia at 1721,1610,1511,1436,1378,1331,1263,1177, 1105,1042,1020, 960, 899, 833, and 693 cmøX-ray diffractogram major peaks (CuK2α):
Example 16 Preparation of D(+)-di-p-toluoyl tartaric acid salt of (+)-trans-l-methyl-3- carbomethoxy-4-(4'-fluorophenyl)piperidine
This salt may be prepared from (+)-trans-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl)piperidine by following the procedure of Example 15 and replacing L(-)-di- p-toluoyl tartaric acid with D(+)-di-p-toluoyl tartaric acid.
Example 17
Resolution of trans-l-methyl-3-carbomethoxy-4-(4'-fluorophenyl)piperidine using seeds
A solution of L(-)-di-p-toluoyl tartaric acid (0.39 g) in ethyl acetate (12.5 ml) was mixed with a solution of racemic trans- 1 -methyl-3 -carbomethoxy-4-(4'-fluorophenyl)piperidine (0.25 g) in o-xylene (12.5 ml) and the mixture was stirred well to give a clear solution. This solution was seeded with (-)-trans-l-methyl-3-carbomethoxy-4-(4'- fluorophenyl)piperidine L(-)-di-p-toluoyl tartrate (5 mg) and stirred for several hours. The
cloudy mixture was stored at 4°C for six days during which time more crystals formed. These were filtered and dried under vacuum.
Yield 0.17g.
Chiral capillary electrophoresis showed that the ratio of (-) trans to (+) trans was 90:10