CA2272373A1 - The preparation of enantiomerically-enriched threo-methylphenidate - Google Patents
The preparation of enantiomerically-enriched threo-methylphenidate Download PDFInfo
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- CA2272373A1 CA2272373A1 CA002272373A CA2272373A CA2272373A1 CA 2272373 A1 CA2272373 A1 CA 2272373A1 CA 002272373 A CA002272373 A CA 002272373A CA 2272373 A CA2272373 A CA 2272373A CA 2272373 A1 CA2272373 A1 CA 2272373A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
A process for increasing the enantiomeric excess of an enantiomerically-enriched mixture of enantiomers of an acid addition salt of threo-methylphenidate, the acid being achiral, comprises crystallisation from, or partial dissolution in, a solvent; and, if necessary, removing any resolving agent that may be present. This process may be preceded by biocatalytic resolution of racemic threo-methylphenidate or ritalinic acid.
Description
TFIREO-METHYLPHENIDATE
. Field of the Invention This invention relates to processes for the preparation of enantiomerically-enriched ' S threo-methylphenidate, and in particular to bioresolution, to the separation of the enantiomers of acid addition salt foams of threo-methylphenidate, and to the enhancement of enantiomeric excess (ee) of one enantiomer in a mixture.
Background of the Invention Methylphenidate is a therapeutic agent that is widely used in the treatment of attention-deficient hyperactivity disorder. It is a controlled substance.
Methylphenidate was first prepared as a mixture of the erythro and threo racemates. US-A-29S7880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo disastereoisomer.
It is now considered that it is the cf threo [or (R,R)] enantiomer that has the preferred therapeutic activity. Uses of this enantiomer are disclosed in WO-A-9703671, WO-A-9703672 and WO-A-9703673, the contents of which are incorporated herein by reference.
The resolution of methylphenidate has been achieved using the expensive resolving agent 1,1'-binaphthjrl-2,2'-diyl hydrogen phosphate, a process reported by Patrick et al, The Journal of Pharmacology and Experimental Therapeutics, 241:152-15 8 ( 1987).
Patrick et al also disclose a modest improvement in the enantiopurity of threo-methylphenidate hydrochloride, by crystallisation) from 95-97% to 99% ee. It is now known that the product is contaminated with resolving agent and/or ritalinic acid; see WO-A-9727176.
WO-A-9727176 and WO-A-973285I disclose that the resolution of methylphenidate has also been achieved, more economically, using either O,O'-diaroyltartaric acids or menthoxyacetic acid. These resolutions provide d threo-methylphenidate in high ee and chemical purity, e.g. containing less than 2%
w/w of resolving agent and/or ritalinic acid.
~ Generally speaking, the racemate and single enantiomers of a .salt of a chiral compound such as threo-methylphenidate have different soiid-state crystalline forms.
Consequently, in solution, such a salt will have an enantiomeric composition which corresponds to its point of maximum solubility (the eutectic composition), and this is dependent upon the solubility of the racemic salt and the single enantiomer salt. The solubility ratio a is given by the ratio of the solubility of the racemate salt divided by the solubility of the single enantiomer salt.
Summary of the Invention One aspect of the present invention is based upon the discovery that certain crystalline salts of threo-methylphenidate, wherein the counterion is achiral, allow for the enhancement of enantiomeric excess (ee) by recrystallisation/crystallisation of partially enriched material in a suitable solvent. In particular, it has surprisingly been found that, in the case of threo-methylphenidate, certain salts of the single enantiomer showed much lower solubility than the corresponding racemate in methanol/TBME (tert-butyl methyl ether).
A second aspect of the present invention is based on the discovery that (R,R)-methylphenidate (1) can be conveniently obtained by means of biocatalytic resolution of a racemic compound of formula 2 (of which one enantomer is shown, for convenience), using a range of hydrolase enzymes.
COZMe COyR
H H i H
Fh ~ ~ H (2) Ph Description of the Invention According to the first aspect of this invention, and by approgr;ate use of partially enantiomerically-enriched salt, crystallisation can be used to give essentially enantiopure threo-methylphenidate. The starting material should be enantiomerically enriched above the eutectic point of the threo-methylphenidate salt. In the case of threo-methylphenidate hydrochloride salt, the eutectic point has been measured to be 25% ee by solubility. That is to say, threo-methylphenidate.HCl salt with a composition of enantiomers greater than 25% ee will, by crystallisation, yield enriched material. Thus, by contrast with the crystallisation reported by Patrick e~ al, sr~pra, threo-methylphenidate salts of significantly WO 98/25902 PCT/GB97/034i8 lower enantiomeric purity, in the range 25-95%, preferably 50-95%, and more preferably 70-95%, can be usefully enriched by direct crystallisation. The process of the invention is therefore of considerable utility with a feedstock of threo-methylphenidate of moderate enantiomeric purity, for example following classical resolution. Any resolving agent that ' S may be present can be removed, e.g. to a level of 2% w/w or below, e.g. no more than 0.5 or i% w/w. Preferably, there is no chemical resolving agent, as in bioresolution or asymmetric synthesis. In the latter two cases at least, the feedstock is uncontaminated by resolving agent. For example, the novel crystallisation process can be used in combination with the novel biocatalytic resolution.
By way of example) the novel bioresolution encompasses the following embodiments:
(i) where R - Me) enandoselective hydrolysis of unwanted (S,S)-methylphenidate (1-threo) affords (S,S)-ritalinic acid, which is easily separated from unreacted (R,R)-methylphenidate by extraction into dilute aqueous alkali.
(ii) where R = Me (or another lower alkyl group), enantioselective hydrolysis of (R,R)-methylphenidate (d-threo) is followed by isolation of (R,R)-ritalinic acid and chemical esterification. To maximise atom utilisation, recycling of the unreacted (S,S)-methylphenidate (I-threo) may be carried out according to the procedure described in WO-A-9728124.
(iii) where R = H, enantioselective esterification of (R,R}-ritalinic acid affords (R,R)-methylphenidate directly.
(iv) where R = H, enantioselective esterification of (S,S)-ritalinic acid, is followed by separation from the (R,R)-antipode, and chemical esterification of the latter.
Compared with classical resolution, the bioresolution process of the present invention provides a number of benefits, including mild reaction conditions (ambient temperature, low environmental impact), cost savings by avoidance of stoichiometric resolving agents, and easier processing (e.g. simple solvent partitioning in selected " cases instead of salt cracking).
As will be apparent from Example 1, suitable biocatalysts can readily be identified. It is preferred that the biocatalyst provides a sufficient degree of optical enrichment that the desired product can be used effectively, e.g. at least 20%
, preferably at least 40 % , and more preferably at least SO % , ee, up to substantially single enantiomer product, e.g. at least 80% or 90% ee.
The novel crystallisation process is also useful to enhance the ee of material of high ee, e.g. at least 95% ee, if that has been produced in chemically-pure form, using a more ei~cient resolving agent for this purpose than I,1'-binaphthyl-2,2'-diyl hydrogen phosphate. Such processes are described in WO-A-9727176 and WO-A-9732851.
The solvent that is used in the invention can readily be chosen by those of ordinary skill in the art. For example, the solvent should be sufficiently polar, e.g.
an alcohol, optionally together with another solvent such as an ether. An aprotic solvent such as acetonitrile or acetone can also be used. A mixture of methanol and TBME is preferred.
The salt used in the invention may have the formula coznne .HX
wherein HX is any achiral acid that forms a suitable salt. The suitability of any salt for use in the invention is readily tested in a crystallisation procedure by one of ordinary skill in the art. HX is preferably a hydrohalide, and X is more preferably Br or Cl.
For the purposes of comparison, racemic dl threo-methyiphenidate.HCl ( 1.0 g) was suspended in 10 m1 of I: I methanol:TBME (7.4 g) and stirred at 25~C for 16 hours.
The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE. This gave 0.640 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.340 g of a white solid. dl Ihreo-methylphenidate.HCl therefore has a solubility of 34 mg per ml of 1:1 MeOH:TBME at 25~C.
This experiment was repeated using 20% ee, 25% ee and single enantiomer d threo-methylphenidate.HCl. These and other solubility results, obtained using essentially the same procedure, are reported in Table 1. In the Tables, MPH = threo-methylphenidate, PPT = precipitate, and MLS = mother liquor.
Table 1 shows solubility measurements for threo-methylphenidate hydrochloride ofdifferent enantiomeric composition (racemate, orenriched in thedenantiomer), and also demonstrates one embodiment of the present invention, namely the ee enhancement achieved by dissolution of the materials in a 1:1 mixture of methanol:TBME at ZS~C, and 5 separation of insoluble material. The point of maximum solubility is at 25% ee, which defines the eutectic composition and the solubiiity ratio a = 34.0/ 17.0 = 2Ø Enhancement of ee is slight when the initial ee is 30%, increasing31.9%, but a progressive to enhancement is observed when the initial ee is higher.
Table 1 ee MPH.HCI ee PPT ee MLS Solubility (mg/per ml) 0% ' - - 34.0 20% 15.9% 25.0% 36.0 25% 19.9% 24.7% 40.0 30% 31.9% 22.6% 33:0 1 S 50% 54.4% 24.3% 27.7 60% 70.7% 25.1 % 26.5 73% 93.0% 46.0% 2S.5 99% - - l7.0 In another embodiment of the present invention, the enrichment procedure may also be effected by simply treating a solution of ~hreo-methylphenidate free base above the eutectic point (>25% ee) with hydrogen chloride in methanol) and isolating the resultant precipitate. The results of a series of experiments are given in Table 2.
Table 2 ee MPH ee PPT ee MLS (% yield) (% yield) 82% -1 threo 97.0% (65%) 36.9% (35%) 87% - I threo 98.0% (69%) 35.7% (23%) 88% - l threo 97.8% (78%) 32.1% (21%) 3 0 91 % - ct threo 99.2% (80%) 43.6% ( 19%) 94% - ct threo 99.7% (86%) 72.3% (8%) 95% - d-threo 99.0% (90%) 36.5% (6%) WO 98/25902 PG"T/GB97/03418 The following Examples illustrate the present invention more specifically.
Example 1 Suitable enzymes for the bioresolution were identified by the following screening protocol:
100 mg of racemic threo-methylphenidate (free base) was dissolved in 100 mM
phosphate buffer adjusted to pH 7. Approximately 50 mg (or equivalent ml) of each candidate enzyme was added and the reactions incubated at 30~C for 24 hours with gentle agitation. For assaying purposes, 40 ~cI of the reaction mixture was dispensed into a vial and allowed to evaporate over KOH in a desiccator overnight. The residue was then dissolved in 1 ml IPA/2 ~ diethylamine solution and undissolved material removed by centrifugation. The enantiomeric composition of the unreacted threo-methylphenidate remaining in solution was analysed by hplc method on the Chirapak AD column using 90: l0:0.2 heptane/IPA/diethylamine at 0.5 ml/min and ~. =227 nm.
Any ritalinic acid also present in the solution was found not to interfere with the detection of the enantiomeric methyl esters.
A representative result was obtained using a-chymotrypsin (Sigma). Its use gave a ratio of enantiomers of unreacted substrate (SS:RR) of 79.5:20.5.
Example 2 al thrco-methylphenidate.HCl enriched in theal enantiomer (73% ee) (0.950 g) was suspended in 10 ml of 1:1 methanol:TBME (7.7 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration) washing the reaction vessel with 10 ml TMBE.
This gave 0.725 g of solid precipitate, with an enantiomeric excess of 93.0%.
The mother liquors were evaporated to dryness to give 0.255 g of a white solid, with an enantiomeric excess of46.0%. ct threo-methylphenidate.HC1 (73% ee) therefore has a solubility of25.5 mg per mi of 1:1 MeOH:TBME at 25~C.
Example 3 cf ~hreo-methylphenidate.HCl enriched in the ct enantiomer (50% ee) (1.00 g) was suspended in 10 ml of 1:1 methanol:TBME (7.9 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE.
This gave 0.710 g of solid precipitate, with an enantiomeric excess of 54.4%.
The mother liquors were evaporated to dryness to give 0.277 g of a white solid, with an enantiomeric excess of 24.3%. al ~hreo-methylphenidate.HCl (S0.0% ee) therefore has a solubility of 27.7 mg per ml of 1:1 MeOH:TBME at 25~C.
xam le 4 d threo-methylphenidate. HCl enriched in the d-enantiomer (60% ee) ( 1.00 g) was suspended in 10 ml of 1:1 methanol:TBME (7.7 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE.
This gave 0.710 g of solid precipitate) with an enantiomeric excess of 70.7%.
The mother liquors were evaporated to dryness to give 0.2b5 g of a white solid, with an enantiomeric excess of25.1%. al threo-methylphenidate.HCl (60% ee) therefore has a solubility of26.5 mg per ml of 1:1 MeOH:TBME at 25~C.
Example 5 ci threo-methylphenidate.HCl enriched in the c~ enantiomer {30% ee) ( 1.00 g) was suspended in 10 ml of 1:1 methanol:TBME(7.7 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE.
This gave 0.655 g of solid precipitate, with an enantiomeric excess of 31.9%.
The mother liquors were evaporated to dryness to give 0.330 g of a white solid, with an enantiomeric excess of 22.6%. ct threo-methylphenidate.HCl (30% ee) therefore has a solubility of 33.0 mg per ml of 1:1 MeOH:TBME at 25~C.
Example 6 l-lhreo-methylphenidate enriched in the 1 enantiomer (88.3% ee) 15.0 g was taken up in 30 ml of methanol) and stirred at 40-50~C whilst bubbling hydrogen chloride gas through the reaction mixture for 10 minutes. The reaction mixture was then heated at reflux for 5 minutes. After this 30 m1 TMBE was added to the reaction mixture which was cooled over one hour to room temperature) and finally at 0~C for 1 hour. The solid material was collected by filtration) washing the reaction vessel with 30 m1 TMBE. This gave 13.50 g (77.8%) of solid precipitate, with an enantiomeric excess of 97.8%. The mother liquors were evaporated to dryness to give 3.60 g of a yellow/orange solid (20.7%), with an enantiomeric excess of 32.1%.
Example 7 d thrco-methylphenidate enriched in the ct enantiomer (9l.3% ee) 11.50 g was taken up in 23 ml of methanol, and stirred at 40-50~C whilst bubbling hydrogen chloride gas through the reaction mixture for 10 minutes. The reaction mixture was then heated at WO 98125902 PC"T/GB97/03418 reflux for 5 minutes. After this 23 ml TMBE was added to the reaction mixture which was cooled over one hour to room temperature, and finally at 0~C for 1 hour. The solid material was collected by filtration, washing the reaction vessel with 23 ml TMBE. This gave 10.60 g (79.7%) of solid precipitate, with an enantiomeric excess of 99.2%. The mother liquors were evaporated to dryness to give 2.50 g of a white solid (18.8%), with an enantiomeric excess of 43.6%.
In order to demonstrate the broader applicability of the invention, the corresponding hydrobromide salt was prepared. Firstly, dl threo-methylphenidate (0.86 g; 3.71 mmol) and ammonium bromide (0.436 g; 4.45 mmol) were taken up in 10 ml methanol and stirred at 25~C for 10 minutes. The solvent was removed undervacuum, this process being repeated a further two times. The resulting white crystalline material was taken up in 25 ml dichloromethane, and filtered through Celite. This gave 0.97 g of a white solid (83.3%). MP = 205.6~C. IR (KBr) v""x = 1730 cni'.
The resultant racemic d! lhreo-methylphenidate.HBr (0.500 g) was suspended in 5 ml of 1:1 methanol:TBME (3.80 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration. This gave 0.355 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.140 g of a white solid. dl threo-methylphenidate.HBr therefore has a solubility of 28 mg per ml of 1:1 MeOH:TBME at 25~C.
Secondly, c~ threo-methylphenidate (0.86 g; 3.71 mmol) and ammonium bromide (0.436 g; 4.45 mmol) were taken up in 10 ml of methanol and stirred at 25~C
for 10 minutes. The solvent was removed under vacuum, this process being repeated a further two times. The resulting white crystalline material was taken up in 25 ml dichloromethane) and filtered through Celite. This gave 0.75 g of a white solid (64.4%). MP =
222.6~C. IR
(KBr) u""x = 1730 cm''.
The resultant single enantiomer c~ threo-methylphenidate.HBr ( 1.0 g) was suspended in 5 ml of 1:1 methanol:TBME (4.00 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration. This gave 0.430 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.070 g of a white solid. d threo methylphenidate.HBr therefore has a solubility of 14.0 mg per ml of 1:1 MeOH:TBME
at 25~C.
. Field of the Invention This invention relates to processes for the preparation of enantiomerically-enriched ' S threo-methylphenidate, and in particular to bioresolution, to the separation of the enantiomers of acid addition salt foams of threo-methylphenidate, and to the enhancement of enantiomeric excess (ee) of one enantiomer in a mixture.
Background of the Invention Methylphenidate is a therapeutic agent that is widely used in the treatment of attention-deficient hyperactivity disorder. It is a controlled substance.
Methylphenidate was first prepared as a mixture of the erythro and threo racemates. US-A-29S7880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo disastereoisomer.
It is now considered that it is the cf threo [or (R,R)] enantiomer that has the preferred therapeutic activity. Uses of this enantiomer are disclosed in WO-A-9703671, WO-A-9703672 and WO-A-9703673, the contents of which are incorporated herein by reference.
The resolution of methylphenidate has been achieved using the expensive resolving agent 1,1'-binaphthjrl-2,2'-diyl hydrogen phosphate, a process reported by Patrick et al, The Journal of Pharmacology and Experimental Therapeutics, 241:152-15 8 ( 1987).
Patrick et al also disclose a modest improvement in the enantiopurity of threo-methylphenidate hydrochloride, by crystallisation) from 95-97% to 99% ee. It is now known that the product is contaminated with resolving agent and/or ritalinic acid; see WO-A-9727176.
WO-A-9727176 and WO-A-973285I disclose that the resolution of methylphenidate has also been achieved, more economically, using either O,O'-diaroyltartaric acids or menthoxyacetic acid. These resolutions provide d threo-methylphenidate in high ee and chemical purity, e.g. containing less than 2%
w/w of resolving agent and/or ritalinic acid.
~ Generally speaking, the racemate and single enantiomers of a .salt of a chiral compound such as threo-methylphenidate have different soiid-state crystalline forms.
Consequently, in solution, such a salt will have an enantiomeric composition which corresponds to its point of maximum solubility (the eutectic composition), and this is dependent upon the solubility of the racemic salt and the single enantiomer salt. The solubility ratio a is given by the ratio of the solubility of the racemate salt divided by the solubility of the single enantiomer salt.
Summary of the Invention One aspect of the present invention is based upon the discovery that certain crystalline salts of threo-methylphenidate, wherein the counterion is achiral, allow for the enhancement of enantiomeric excess (ee) by recrystallisation/crystallisation of partially enriched material in a suitable solvent. In particular, it has surprisingly been found that, in the case of threo-methylphenidate, certain salts of the single enantiomer showed much lower solubility than the corresponding racemate in methanol/TBME (tert-butyl methyl ether).
A second aspect of the present invention is based on the discovery that (R,R)-methylphenidate (1) can be conveniently obtained by means of biocatalytic resolution of a racemic compound of formula 2 (of which one enantomer is shown, for convenience), using a range of hydrolase enzymes.
COZMe COyR
H H i H
Fh ~ ~ H (2) Ph Description of the Invention According to the first aspect of this invention, and by approgr;ate use of partially enantiomerically-enriched salt, crystallisation can be used to give essentially enantiopure threo-methylphenidate. The starting material should be enantiomerically enriched above the eutectic point of the threo-methylphenidate salt. In the case of threo-methylphenidate hydrochloride salt, the eutectic point has been measured to be 25% ee by solubility. That is to say, threo-methylphenidate.HCl salt with a composition of enantiomers greater than 25% ee will, by crystallisation, yield enriched material. Thus, by contrast with the crystallisation reported by Patrick e~ al, sr~pra, threo-methylphenidate salts of significantly WO 98/25902 PCT/GB97/034i8 lower enantiomeric purity, in the range 25-95%, preferably 50-95%, and more preferably 70-95%, can be usefully enriched by direct crystallisation. The process of the invention is therefore of considerable utility with a feedstock of threo-methylphenidate of moderate enantiomeric purity, for example following classical resolution. Any resolving agent that ' S may be present can be removed, e.g. to a level of 2% w/w or below, e.g. no more than 0.5 or i% w/w. Preferably, there is no chemical resolving agent, as in bioresolution or asymmetric synthesis. In the latter two cases at least, the feedstock is uncontaminated by resolving agent. For example, the novel crystallisation process can be used in combination with the novel biocatalytic resolution.
By way of example) the novel bioresolution encompasses the following embodiments:
(i) where R - Me) enandoselective hydrolysis of unwanted (S,S)-methylphenidate (1-threo) affords (S,S)-ritalinic acid, which is easily separated from unreacted (R,R)-methylphenidate by extraction into dilute aqueous alkali.
(ii) where R = Me (or another lower alkyl group), enantioselective hydrolysis of (R,R)-methylphenidate (d-threo) is followed by isolation of (R,R)-ritalinic acid and chemical esterification. To maximise atom utilisation, recycling of the unreacted (S,S)-methylphenidate (I-threo) may be carried out according to the procedure described in WO-A-9728124.
(iii) where R = H, enantioselective esterification of (R,R}-ritalinic acid affords (R,R)-methylphenidate directly.
(iv) where R = H, enantioselective esterification of (S,S)-ritalinic acid, is followed by separation from the (R,R)-antipode, and chemical esterification of the latter.
Compared with classical resolution, the bioresolution process of the present invention provides a number of benefits, including mild reaction conditions (ambient temperature, low environmental impact), cost savings by avoidance of stoichiometric resolving agents, and easier processing (e.g. simple solvent partitioning in selected " cases instead of salt cracking).
As will be apparent from Example 1, suitable biocatalysts can readily be identified. It is preferred that the biocatalyst provides a sufficient degree of optical enrichment that the desired product can be used effectively, e.g. at least 20%
, preferably at least 40 % , and more preferably at least SO % , ee, up to substantially single enantiomer product, e.g. at least 80% or 90% ee.
The novel crystallisation process is also useful to enhance the ee of material of high ee, e.g. at least 95% ee, if that has been produced in chemically-pure form, using a more ei~cient resolving agent for this purpose than I,1'-binaphthyl-2,2'-diyl hydrogen phosphate. Such processes are described in WO-A-9727176 and WO-A-9732851.
The solvent that is used in the invention can readily be chosen by those of ordinary skill in the art. For example, the solvent should be sufficiently polar, e.g.
an alcohol, optionally together with another solvent such as an ether. An aprotic solvent such as acetonitrile or acetone can also be used. A mixture of methanol and TBME is preferred.
The salt used in the invention may have the formula coznne .HX
wherein HX is any achiral acid that forms a suitable salt. The suitability of any salt for use in the invention is readily tested in a crystallisation procedure by one of ordinary skill in the art. HX is preferably a hydrohalide, and X is more preferably Br or Cl.
For the purposes of comparison, racemic dl threo-methyiphenidate.HCl ( 1.0 g) was suspended in 10 m1 of I: I methanol:TBME (7.4 g) and stirred at 25~C for 16 hours.
The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE. This gave 0.640 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.340 g of a white solid. dl Ihreo-methylphenidate.HCl therefore has a solubility of 34 mg per ml of 1:1 MeOH:TBME at 25~C.
This experiment was repeated using 20% ee, 25% ee and single enantiomer d threo-methylphenidate.HCl. These and other solubility results, obtained using essentially the same procedure, are reported in Table 1. In the Tables, MPH = threo-methylphenidate, PPT = precipitate, and MLS = mother liquor.
Table 1 shows solubility measurements for threo-methylphenidate hydrochloride ofdifferent enantiomeric composition (racemate, orenriched in thedenantiomer), and also demonstrates one embodiment of the present invention, namely the ee enhancement achieved by dissolution of the materials in a 1:1 mixture of methanol:TBME at ZS~C, and 5 separation of insoluble material. The point of maximum solubility is at 25% ee, which defines the eutectic composition and the solubiiity ratio a = 34.0/ 17.0 = 2Ø Enhancement of ee is slight when the initial ee is 30%, increasing31.9%, but a progressive to enhancement is observed when the initial ee is higher.
Table 1 ee MPH.HCI ee PPT ee MLS Solubility (mg/per ml) 0% ' - - 34.0 20% 15.9% 25.0% 36.0 25% 19.9% 24.7% 40.0 30% 31.9% 22.6% 33:0 1 S 50% 54.4% 24.3% 27.7 60% 70.7% 25.1 % 26.5 73% 93.0% 46.0% 2S.5 99% - - l7.0 In another embodiment of the present invention, the enrichment procedure may also be effected by simply treating a solution of ~hreo-methylphenidate free base above the eutectic point (>25% ee) with hydrogen chloride in methanol) and isolating the resultant precipitate. The results of a series of experiments are given in Table 2.
Table 2 ee MPH ee PPT ee MLS (% yield) (% yield) 82% -1 threo 97.0% (65%) 36.9% (35%) 87% - I threo 98.0% (69%) 35.7% (23%) 88% - l threo 97.8% (78%) 32.1% (21%) 3 0 91 % - ct threo 99.2% (80%) 43.6% ( 19%) 94% - ct threo 99.7% (86%) 72.3% (8%) 95% - d-threo 99.0% (90%) 36.5% (6%) WO 98/25902 PG"T/GB97/03418 The following Examples illustrate the present invention more specifically.
Example 1 Suitable enzymes for the bioresolution were identified by the following screening protocol:
100 mg of racemic threo-methylphenidate (free base) was dissolved in 100 mM
phosphate buffer adjusted to pH 7. Approximately 50 mg (or equivalent ml) of each candidate enzyme was added and the reactions incubated at 30~C for 24 hours with gentle agitation. For assaying purposes, 40 ~cI of the reaction mixture was dispensed into a vial and allowed to evaporate over KOH in a desiccator overnight. The residue was then dissolved in 1 ml IPA/2 ~ diethylamine solution and undissolved material removed by centrifugation. The enantiomeric composition of the unreacted threo-methylphenidate remaining in solution was analysed by hplc method on the Chirapak AD column using 90: l0:0.2 heptane/IPA/diethylamine at 0.5 ml/min and ~. =227 nm.
Any ritalinic acid also present in the solution was found not to interfere with the detection of the enantiomeric methyl esters.
A representative result was obtained using a-chymotrypsin (Sigma). Its use gave a ratio of enantiomers of unreacted substrate (SS:RR) of 79.5:20.5.
Example 2 al thrco-methylphenidate.HCl enriched in theal enantiomer (73% ee) (0.950 g) was suspended in 10 ml of 1:1 methanol:TBME (7.7 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration) washing the reaction vessel with 10 ml TMBE.
This gave 0.725 g of solid precipitate, with an enantiomeric excess of 93.0%.
The mother liquors were evaporated to dryness to give 0.255 g of a white solid, with an enantiomeric excess of46.0%. ct threo-methylphenidate.HC1 (73% ee) therefore has a solubility of25.5 mg per mi of 1:1 MeOH:TBME at 25~C.
Example 3 cf ~hreo-methylphenidate.HCl enriched in the ct enantiomer (50% ee) (1.00 g) was suspended in 10 ml of 1:1 methanol:TBME (7.9 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE.
This gave 0.710 g of solid precipitate, with an enantiomeric excess of 54.4%.
The mother liquors were evaporated to dryness to give 0.277 g of a white solid, with an enantiomeric excess of 24.3%. al ~hreo-methylphenidate.HCl (S0.0% ee) therefore has a solubility of 27.7 mg per ml of 1:1 MeOH:TBME at 25~C.
xam le 4 d threo-methylphenidate. HCl enriched in the d-enantiomer (60% ee) ( 1.00 g) was suspended in 10 ml of 1:1 methanol:TBME (7.7 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE.
This gave 0.710 g of solid precipitate) with an enantiomeric excess of 70.7%.
The mother liquors were evaporated to dryness to give 0.2b5 g of a white solid, with an enantiomeric excess of25.1%. al threo-methylphenidate.HCl (60% ee) therefore has a solubility of26.5 mg per ml of 1:1 MeOH:TBME at 25~C.
Example 5 ci threo-methylphenidate.HCl enriched in the c~ enantiomer {30% ee) ( 1.00 g) was suspended in 10 ml of 1:1 methanol:TBME(7.7 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE.
This gave 0.655 g of solid precipitate, with an enantiomeric excess of 31.9%.
The mother liquors were evaporated to dryness to give 0.330 g of a white solid, with an enantiomeric excess of 22.6%. ct threo-methylphenidate.HCl (30% ee) therefore has a solubility of 33.0 mg per ml of 1:1 MeOH:TBME at 25~C.
Example 6 l-lhreo-methylphenidate enriched in the 1 enantiomer (88.3% ee) 15.0 g was taken up in 30 ml of methanol) and stirred at 40-50~C whilst bubbling hydrogen chloride gas through the reaction mixture for 10 minutes. The reaction mixture was then heated at reflux for 5 minutes. After this 30 m1 TMBE was added to the reaction mixture which was cooled over one hour to room temperature) and finally at 0~C for 1 hour. The solid material was collected by filtration) washing the reaction vessel with 30 m1 TMBE. This gave 13.50 g (77.8%) of solid precipitate, with an enantiomeric excess of 97.8%. The mother liquors were evaporated to dryness to give 3.60 g of a yellow/orange solid (20.7%), with an enantiomeric excess of 32.1%.
Example 7 d thrco-methylphenidate enriched in the ct enantiomer (9l.3% ee) 11.50 g was taken up in 23 ml of methanol, and stirred at 40-50~C whilst bubbling hydrogen chloride gas through the reaction mixture for 10 minutes. The reaction mixture was then heated at WO 98125902 PC"T/GB97/03418 reflux for 5 minutes. After this 23 ml TMBE was added to the reaction mixture which was cooled over one hour to room temperature, and finally at 0~C for 1 hour. The solid material was collected by filtration, washing the reaction vessel with 23 ml TMBE. This gave 10.60 g (79.7%) of solid precipitate, with an enantiomeric excess of 99.2%. The mother liquors were evaporated to dryness to give 2.50 g of a white solid (18.8%), with an enantiomeric excess of 43.6%.
In order to demonstrate the broader applicability of the invention, the corresponding hydrobromide salt was prepared. Firstly, dl threo-methylphenidate (0.86 g; 3.71 mmol) and ammonium bromide (0.436 g; 4.45 mmol) were taken up in 10 ml methanol and stirred at 25~C for 10 minutes. The solvent was removed undervacuum, this process being repeated a further two times. The resulting white crystalline material was taken up in 25 ml dichloromethane, and filtered through Celite. This gave 0.97 g of a white solid (83.3%). MP = 205.6~C. IR (KBr) v""x = 1730 cni'.
The resultant racemic d! lhreo-methylphenidate.HBr (0.500 g) was suspended in 5 ml of 1:1 methanol:TBME (3.80 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration. This gave 0.355 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.140 g of a white solid. dl threo-methylphenidate.HBr therefore has a solubility of 28 mg per ml of 1:1 MeOH:TBME at 25~C.
Secondly, c~ threo-methylphenidate (0.86 g; 3.71 mmol) and ammonium bromide (0.436 g; 4.45 mmol) were taken up in 10 ml of methanol and stirred at 25~C
for 10 minutes. The solvent was removed under vacuum, this process being repeated a further two times. The resulting white crystalline material was taken up in 25 ml dichloromethane) and filtered through Celite. This gave 0.75 g of a white solid (64.4%). MP =
222.6~C. IR
(KBr) u""x = 1730 cm''.
The resultant single enantiomer c~ threo-methylphenidate.HBr ( 1.0 g) was suspended in 5 ml of 1:1 methanol:TBME (4.00 g) and stirred at 25~C for 16 hours. The solid material was collected by filtration. This gave 0.430 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.070 g of a white solid. d threo methylphenidate.HBr therefore has a solubility of 14.0 mg per ml of 1:1 MeOH:TBME
at 25~C.
Claims (27)
1. A process for increasing the excess of one enantiomer in a mixture of enantiomers of an acid addition salt of threo-methylphenidate, wherein the acid forming the salt is achiral, the starting mixture is enantiomerically enriched above the eutectic point of the salt, and the eutectic point is at an enantiomeric excess of the one enantiomer; the process comprising crystallisation from, or partial dissolution in, a solvent; and, if necessary, removing any resolving agent that may be present.
2. A process according to claim 1, wherein crystallisation follows dissolution of the pre-formed acid addition salt in a solvent.
3. A process according to claim 1, wherein crystallisation follows addition of the acid to a solution of threo-methylphenidate free base.
4. A process according to any preceding claim, wherein, prior to crystallisation of the acid addition salt, the initial ee is at least 25% ee.
5. A process according to claim 4, wherein the initial ee is 25 to 95%.
6. A process according to claim 4, wherein the initial ee is 50 to 95%.
7. A process according to claim 4, wherein the initial ee is 70 to 95%.
8. A process according to any preceding claim, wherein the mixture of enantiomers contains less than 2% w/w resolving agent.
9. A process according to any preceding claim, wherein the acid is a hydrohalide.
10. A process according to claim 9, wherein the acid is HCI.
11. A process according to claim 9, wherein the acid is HBr.
12. A process according to any preceding claim, for the preparation of d-threo methylphenidate hydrochloride of enantiomeric purity in excess of 98% ee.
13. A process according to any preceding claim, which follows classical resolution and, optionally, removal of resolving agent.
14. A process according to any of claims 1 to 12, which follows asymmetric synthesis.
15. A process according to any of claims 1 to 12, which follows bioresolution.
16. A process according to claim 15, wherein the bioresolution is of a racemic compound of the formula wherein the relative stereochemistry is threo, and R is H or methyl.
17. A process according to claim 16, wherein racemic threo-methylphenidate is subjected to hydrolysis in the presence of an enzyme that displays enantioselectivity.
18. A process according to claim 16, wherein racemic ritalinic acid is subjected to esterification in the presence of an enzyme that displays enantioselectivity.
19. A process according to claim 17 or claim 18, which additionally comprises conventional chemical esterification of (R,R)-ritalinic acid.
20. A process according to any of claims 17 to 19, wherein the enzyme is .alpha.-chymotrypsin (bovine pancreas).
21. A process according to any of claims 17 to 20, wherein the enzyme is in immobilised form.
22. A process for preparing enantiomerically enriched d threo-methylphenidate, which comprises biocatalytic resolution of a racemic compound of the formula wherein the relative stereochemistry is threo, and R is H or methyl.
23. A process according to claim 22, wherein racemic threo-methylphenidate is subjected to hydrolysis in the presence of an enzyme that displays enantioselectivity.
24. A process according to claim 22, wherein racemic ritalinic acid is subjected to esterification in the presence of an enzyme that displays enantioselectivity.
25. A process according to claim 23 or claim 24, which additionally comprises conventional chemical esterification of (R,R)-ritalinic acid.
26. A process according to any of claims 23 to 25, wherein the enzyme is .alpha.-chymotrypsin (bovine pancreas).
27. A process according to any of claims 23 to 26, wherein the enzyme is in immobilised form.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9625972.6A GB9625972D0 (en) | 1996-12-13 | 1996-12-13 | Bioresolution |
| GB9625972.6 | 1996-12-13 | ||
| GB9712298.0 | 1997-06-12 | ||
| GBGB9712298.0A GB9712298D0 (en) | 1997-06-12 | 1997-06-12 | Crystallisation |
| PCT/GB1997/003418 WO1998025902A1 (en) | 1996-12-13 | 1997-12-11 | The preparation of enantiomerically-enriched threo-methylphenidate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2272373A1 true CA2272373A1 (en) | 1998-06-18 |
Family
ID=26310627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002272373A Abandoned CA2272373A1 (en) | 1996-12-13 | 1997-12-11 | The preparation of enantiomerically-enriched threo-methylphenidate |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0948484A1 (en) |
| JP (1) | JP2001506621A (en) |
| AU (1) | AU7847098A (en) |
| CA (1) | CA2272373A1 (en) |
| CZ (1) | CZ206299A3 (en) |
| HU (1) | HUP0001604A3 (en) |
| NO (1) | NO992875L (en) |
| PL (1) | PL334136A1 (en) |
| WO (1) | WO1998025902A1 (en) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6486177B2 (en) | 1995-12-04 | 2002-11-26 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
| US6100401A (en) * | 1998-04-20 | 2000-08-08 | Novartris Ag | Process for preparing the d-threo isomer of methylphenidate hydrochloride |
| US6162919A (en) * | 1998-12-03 | 2000-12-19 | Novartis Ag | Process for preparing the d-threo isomer of methylphenidate hydrochloride |
| US6395752B1 (en) * | 1999-03-04 | 2002-05-28 | Pharmaquest Limited | Method of treating depression using 1-threo-methylphenidate |
| US6127385A (en) * | 1999-03-04 | 2000-10-03 | Pharmaquest Limited | Method of treating depression using l-threo-methylphenidate |
| US6025502A (en) * | 1999-03-19 | 2000-02-15 | The Trustees Of The University Of Pennsylvania | Enantopselective synthesis of methyl phenidate |
| US6221883B1 (en) * | 2000-04-12 | 2001-04-24 | Ross Baldessarini | Method of dopamine inhibition using l-threo-methylphenidate |
| EP1163907B1 (en) * | 2000-06-17 | 2006-04-12 | Pharmaquest Limited | Use of l-threo-methylphenidate for the manufacture of a medicament for the treatment of depression |
| US7247730B2 (en) * | 2003-03-07 | 2007-07-24 | Isp Investments Inc. | Process for the preparation of dexmethylphenidate hydrochloride |
| US7897777B2 (en) | 2007-01-05 | 2011-03-01 | Archimica, Inc. | Process of enantiomeric resolution of D,L-(±)-threo-methylphenidate |
| WO2010128517A1 (en) | 2009-05-07 | 2010-11-11 | Malladi Drugs & Pharmaceuticals Ltd. | Improved process for the preparation of d-threo-ritalinic acid hydrochloride by resolution of dl-threo-ritalinic acid using chiral carboxylic acid |
| ES2542433T3 (en) | 2010-12-17 | 2015-08-05 | Rhodes Technologies | Synthesis at low temperature of methylphenidate hydrochloride |
| US9283214B2 (en) | 2011-03-23 | 2016-03-15 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| US10905652B2 (en) | 2011-03-23 | 2021-02-02 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
| US10292937B2 (en) | 2011-03-23 | 2019-05-21 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
| US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
| US11241391B2 (en) | 2011-03-23 | 2022-02-08 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| DK4011364T3 (en) | 2011-03-23 | 2024-03-18 | Ironshore Pharmaceuticals & Dev Inc | Methods and compositions for treating ADD (Attention Deficit Disorder) |
| US9233924B2 (en) | 2014-03-11 | 2016-01-12 | Ampac Fine Chemicals Llc | Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof |
| US10081597B2 (en) | 2014-06-27 | 2018-09-25 | Embio Limited | Process for preparation of dexmethylphenidate hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH02190195A (en) * | 1989-01-19 | 1990-07-26 | Rikagaku Kenkyusho | Production of optically active propionic acid ester compound |
| JPH02273196A (en) * | 1989-03-08 | 1990-11-07 | Wisconsin Alumni Res Found | Method for improving enantio-selectivity in biocatalytic resolution of racemic compound |
| JP3431204B2 (en) * | 1993-04-22 | 2003-07-28 | 塩野義製薬株式会社 | Norbornane type ester hydrolase |
| BE1007297A3 (en) * | 1993-07-19 | 1995-05-09 | Dsm Nv | OPTICAL METHOD FOR THE PREPARATION OF ACTIVE alcohols and esters, alcohols and esters APPLIED AND WILLING TO SUCH METHODS. |
| DE4420751A1 (en) * | 1994-06-15 | 1995-12-21 | Basf Ag | Process for the preparation of enantiomerically pure lactams |
-
1997
- 1997-12-11 HU HU0001604A patent/HUP0001604A3/en unknown
- 1997-12-11 PL PL97334136A patent/PL334136A1/en unknown
- 1997-12-11 EP EP97949034A patent/EP0948484A1/en not_active Withdrawn
- 1997-12-11 CZ CZ992062A patent/CZ206299A3/en unknown
- 1997-12-11 WO PCT/GB1997/003418 patent/WO1998025902A1/en not_active Application Discontinuation
- 1997-12-11 CA CA002272373A patent/CA2272373A1/en not_active Abandoned
- 1997-12-11 AU AU78470/98A patent/AU7847098A/en not_active Abandoned
- 1997-12-11 JP JP52637898A patent/JP2001506621A/en active Pending
-
1999
- 1999-06-11 NO NO992875A patent/NO992875L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO992875D0 (en) | 1999-06-11 |
| PL334136A1 (en) | 2000-02-14 |
| AU7847098A (en) | 1998-07-03 |
| CZ206299A3 (en) | 1999-09-15 |
| JP2001506621A (en) | 2001-05-22 |
| HUP0001604A3 (en) | 2003-03-28 |
| EP0948484A1 (en) | 1999-10-13 |
| WO1998025902A1 (en) | 1998-06-18 |
| HUP0001604A2 (en) | 2000-10-28 |
| NO992875L (en) | 1999-06-14 |
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