US20020019535A1 - Resolution of ritalinic acid salt - Google Patents
Resolution of ritalinic acid salt Download PDFInfo
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- US20020019535A1 US20020019535A1 US09/487,071 US48707100A US2002019535A1 US 20020019535 A1 US20020019535 A1 US 20020019535A1 US 48707100 A US48707100 A US 48707100A US 2002019535 A1 US2002019535 A1 US 2002019535A1
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- threo
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- INGSNVSERUZOAK-UHFFFAOYSA-N ritalinic acid Chemical class C=1C=CC=CC=1C(C(=O)O)C1CCCCN1 INGSNVSERUZOAK-UHFFFAOYSA-N 0.000 title description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- DUGOZIWVEXMGBE-CHWSQXEVSA-N dexmethylphenidate Chemical compound C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-CHWSQXEVSA-N 0.000 claims abstract description 3
- 229960001042 dexmethylphenidate Drugs 0.000 claims abstract description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 10
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical group CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000000129 anionic group Chemical group 0.000 claims 1
- 150000001450 anions Chemical class 0.000 claims 1
- 125000002091 cationic group Chemical group 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 239000012022 methylating agents Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229960001344 methylphenidate Drugs 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- DUGOZIWVEXMGBE-OLZOCXBDSA-N methyl (S)-phenyl[(R)-piperidin-2-yl]acetate Chemical compound C([C@@H]1[C@@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-OLZOCXBDSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SCUMDQFFZZGUQY-MNMPKAIFSA-N (2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetic acid hydrochloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)O)C=2C=CC=CC=2)CCCN1 SCUMDQFFZZGUQY-MNMPKAIFSA-N 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- INGSNVSERUZOAK-VXGBXAGGSA-N (2r)-2-phenyl-2-[(2r)-piperidin-1-ium-2-yl]acetate Chemical compound C([C@@H]1[C@H](C(=O)O)C=2C=CC=CC=2)CCCN1 INGSNVSERUZOAK-VXGBXAGGSA-N 0.000 description 1
- SCUMDQFFZZGUQY-FXMYHANSSA-N (2s)-2-phenyl-2-[(2s)-piperidin-2-yl]acetic acid;hydrochloride Chemical compound Cl.C([C@H]1[C@@H](C(=O)O)C=2C=CC=CC=2)CCCN1 SCUMDQFFZZGUQY-FXMYHANSSA-N 0.000 description 1
- JEHUZVBIUCAMRZ-UHFFFAOYSA-N 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate Chemical compound O1P(O)(=O)OC2=CC=C(C=CC=C3)C3=C2C2=C1C=CC1=CC=CC=C21 JEHUZVBIUCAMRZ-UHFFFAOYSA-N 0.000 description 1
- RTCUCQWIICFPOD-UHFFFAOYSA-N 1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C(C(N)C)=CC=CC2=C1 RTCUCQWIICFPOD-UHFFFAOYSA-N 0.000 description 1
- YEHGSOZIZRABBU-UHFFFAOYSA-N 1-phenylethanamine;hydrochloride Chemical compound [Cl-].CC([NH3+])C1=CC=CC=C1 YEHGSOZIZRABBU-UHFFFAOYSA-N 0.000 description 1
- CILPHQCEVYJUDN-UHFFFAOYSA-N 2-(5-methyl-2-propan-2-ylcyclohexyl)oxyacetic acid Chemical compound CC(C)C1CCC(C)CC1OCC(O)=O CILPHQCEVYJUDN-UHFFFAOYSA-N 0.000 description 1
- GBEXQDZPQAUKST-UHFFFAOYSA-O CC([NH3+])C1=CC=CC=C1.O=C([O-])C(C1=CC=CC=C1)C1CCCC[NH2+]1.[Cl-] Chemical compound CC([NH3+])C1=CC=CC=C1.O=C([O-])C(C1=CC=CC=C1)C1CCCC[NH2+]1.[Cl-] GBEXQDZPQAUKST-UHFFFAOYSA-O 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 229940125368 controlled substance Drugs 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- GIZSHQYTTBQKOQ-UHFFFAOYSA-N threo-Syringoylglycerol Chemical compound COC1=CC(C(O)C(O)CO)=CC(OC)=C1O GIZSHQYTTBQKOQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Definitions
- This invention relates to an economic process for the manufacture of a single isomer of a precursor to d-threo-methylphenidate.
- 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 [R*S*] and threo [R*R*] racemates.
- U.S. Pat. No. 2,957,880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereoisomer. It is now considered that it is the d-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.
- O,O′-diaroyltartaric acid or menthoxyacetic acid More efficient resolutions, using a O,O′-diaroyltartaric acid or menthoxyacetic acid, are disclosed in WO-A-9727176 and in PCT/GB97/00643, the contents of which are incorporated by reference; in particular, the use of O,O′-di-p-toluoyltartaric acid allows the diastereoisomeric salts to be very readily separated, to give the desired enantiomer in high enantiomeric excess and high chemical purity.
- Ritalinic acid might be a target, and is a common intermediate, in threo form, in synthesis preceding or following the two respective resolutions described above.
- U.S. Pat. No. 2,957,880 discloses single isomer ritalinic acid hydrochloride. It is prepared (see Example 6) from the corresponding acid amide.
- the present invention is based on the surprising discovery that, although ritalinic acid will not undergo any effective degree of resolution with any of a wide range of resolving agents, a salt thereof is an effective substrate for resolution, e.g. with a chiral base.
- a salt thereof is an effective substrate for resolution, e.g. with a chiral base.
- threo-ritalinic acid hydrochloride is resolved with ( ⁇ )-1-phenylethyl amine.
- the chiral base may form a novel double salt.
- the salt that is the substrate for resolution according to this invention may be prepared by base hydrolysis of methylphenidate, using NaOH or another hydroxide (MOH).
- a suitable acid salt may then be prepared by adding an acid (HX) that releases M from the resultant salt (e.g. a metal or ammonium salt) of ritalinic acid. On passing the isoelectric point, it appears that the piperidine N atom is protonated.
- preparation of salts may be via acid hydrolysis of methylphenidate.
- the resolution is conducted using conditions that are generally known in the art.
- suitable chiral bases are 1-phenylethylamine, and also 1-(1-naphthyl) ethylamine, cinchonine, cinchonidine and N-methyl-D-glucamine.
- the use of, say, ( ⁇ )-1-phenylethylamine gives the preferred d-threo-enantiomer of ritalinic acid salt. That can be converted to d-threo-methylphenidate hydrochloride by reaction with methanol and HCl, with heating.
- Salts that are substrates for resolution according to this invention have good or at least adequate solubility in various solvents, especially polar solvents, including aqueous systems. Adjustment of pH, e.g. by adding acid (which may be ritalinic acid), can enhance solubility.
- Chiral HPLC analysis showed the crystals to comprise a diastereoisomeric salt enriched in d-threo-ritalinic acid, of 77% ee, and the mother liquors containing the opposite diastereoisomer enriched in 1-threo-ritalinic acid, of at least 23% ee.
- a crystalline ritalinate salt is formed when ritalinic acid hydrochloride is mixed with 1-phenylethylamine but does not form when the ritalinic free amino-acid is mixed with 1-phenylethylamine. NMR shows that this salt contains ritalinate and is thus not simply 1-phenylethylamine hydrochloride. From these observations, it is deduced that the salt is the double salt depicted below. The salt is also a hydrate, since only a gelatinous precipitate is formed in anhydrous ethanol, whereas in 95% ethanol/5% water white crystals are formed.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Investigating Or Analyzing Materials By The Use Of Ultrasonic Waves (AREA)
- Gyroscopes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
A process for preparing an enantiomerically-enriched form of threo-ritalinic acid, which comprises resolving a mixture of enantiomers of a salt of the acid, said salt being formed with an achiral acid or base, using a chiral resolving agent. The resolved salt can be esterified, to give the therapeutic agent d-threo-methylphenidate.
Description
- This invention relates to an economic process for the manufacture of a single isomer of a precursor to d-threo-methylphenidate.
- 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 [R*S*] and threo [R*R*] racemates. U.S. Pat. No. 2,957,880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereoisomer. It is now considered that it is the d-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 threo methylphenidate can be achieved using the expensive resolving agent 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, a process first reported by Patrick et al, The Journal of Pharmacology and Experimental Therapeutics, 241:152-158 (1987). More efficient resolutions, using a O,O′-diaroyltartaric acid or menthoxyacetic acid, are disclosed in WO-A-9727176 and in PCT/GB97/00643, the contents of which are incorporated by reference; in particular, the use of O,O′-di-p-toluoyltartaric acid allows the diastereoisomeric salts to be very readily separated, to give the desired enantiomer in high enantiomeric excess and high chemical purity.
- In an alternative approach, disclosed in U.S. Pat. No. 2,957,880, the amide of erythro methylphenidate (i.e. as —CONH 2 instead of —CO2Me) is resolved using tartaric acid. However, this resolution must be followed by amide hydrolysis, and equilibration at the benzylic centre, to give the threo isomer of the carboxylic acid which is esterified.
- It would be desirable to find a satisfactory substrate for resolution that did not involve handling the active drug. Ritalinic acid might be a target, and is a common intermediate, in threo form, in synthesis preceding or following the two respective resolutions described above.
- U.S. Pat. No. 2,957,880 discloses single isomer ritalinic acid hydrochloride. It is prepared (see Example 6) from the corresponding acid amide.
- The present invention is based on the surprising discovery that, although ritalinic acid will not undergo any effective degree of resolution with any of a wide range of resolving agents, a salt thereof is an effective substrate for resolution, e.g. with a chiral base. In a particular preferred embodiment of the invention, threo-ritalinic acid hydrochloride is resolved with (−)-1-phenylethyl amine. The chiral base may form a novel double salt.
- For the purposes of illustration at least, the salt that is the substrate for resolution according to this invention may be prepared by base hydrolysis of methylphenidate, using NaOH or another hydroxide (MOH). A suitable acid salt may then be prepared by adding an acid (HX) that releases M from the resultant salt (e.g. a metal or ammonium salt) of ritalinic acid. On passing the isoelectric point, it appears that the piperidine N atom is protonated. Alternatively, preparation of salts may be via acid hydrolysis of methylphenidate.
- The resolution is conducted using conditions that are generally known in the art. Examples of suitable chiral bases are 1-phenylethylamine, and also 1-(1-naphthyl) ethylamine, cinchonine, cinchonidine and N-methyl-D-glucamine. The use of, say, (−)-1-phenylethylamine gives the preferred d-threo-enantiomer of ritalinic acid salt. That can be converted to d-threo-methylphenidate hydrochloride by reaction with methanol and HCl, with heating.
- Salts that are substrates for resolution according to this invention have good or at least adequate solubility in various solvents, especially polar solvents, including aqueous systems. Adjustment of pH, e.g. by adding acid (which may be ritalinic acid), can enhance solubility.
- The following Example illustrates the invention.
- A solution of dl-threo-methylphenidate (1 g) in water (25 ml) and conc. HCl (5 ml) was heated under reflux for 3 h. The clear solution was evaporated to dryness, to give a dl-threo-ritalinic acid hydrochloride as a white solid.
- Resolution was performed using this salt. The salt (175 mg; 0.8 mmol) was placed in a 10 ml round-bottom flask. Ethanol (5 ml) was added, to give a clear solution. (−)-1-Phenylethylamine (0.1 ml; 0.8 mmol) was added. A gelatinous precipitate formed after a few minutes. Water (15 drops) was added, and the mixture stirred for 2 h. White crystals formed within 1 h. Following stirring overnight, crystals (40 mg) were collected on a sinter. Chiral HPLC analysis showed the crystals to comprise a diastereoisomeric salt enriched in d-threo-ritalinic acid, of 77% ee, and the mother liquors containing the opposite diastereoisomer enriched in 1-threo-ritalinic acid, of at least 23% ee.
- A crystalline ritalinate salt is formed when ritalinic acid hydrochloride is mixed with 1-phenylethylamine but does not form when the ritalinic free amino-acid is mixed with 1-phenylethylamine. NMR shows that this salt contains ritalinate and is thus not simply 1-phenylethylamine hydrochloride. From these observations, it is deduced that the salt is the double salt depicted below. The salt is also a hydrate, since only a gelatinous precipitate is formed in anhydrous ethanol, whereas in 95% ethanol/5% water white crystals are formed.
Claims (17)
1. A process for preparing an enantiomerically-enriched form of threo-ritalinic acid, which comprises resolving a mixture of enantiomers of a salt of the acid, said salt being formed with an achiral acid or base, using a single enantiomer chiral resolving agent that is basic when said salt is formed with an achiral acid or that is acidic when said salt is formed with an achiral base.
2. The process according to claim 1 , wherein said salt is formed with an achiral amine or acid.
3. The process according to claim 2 , wherein said salt is formed with an acid of the formula HX, X being any anion.
4. The process according to claim 3 , wherein said salt is the hydrochloride.
5. The process according to claim 1 , wherein the enrichment is at least 70%.
6. The process according to claim 3 , wherein the resolving agent is an amine.
7. The process according to claim 6 , wherein the amine is (−)-1-phenylethylamine.
8. The process according to claim 1 , wherein the d-enantiomer is enantiomerically-enriched.
9. A process for preparing d-threo-methylphenidate, which comprises conducting a process according to claim 8 and then subjecting the product to reaction with methanol or esterification with a methylating agent.
10. A double salt of threo-ritalinic acid, predominantly as a single enantiomer thereof, comprising one anionic counterion and one cationic counterion, wherein one of said counterion is achiral and the other is derived from a single enantiomer chiral resolving agent.
11. The double salt according to claim 10 , wherein the achiral acid or base is as defined in claim 2 .
12. The double salt according to claim 10 , wherein the chiral resolving agent is as defined in claim 6 .
13. The double salt according to claim 10 , wherein the achiral acid or base is as defined in claim 3 .
14. The double salt according to claim 10 , wherein the achiral acid or base is as defined in claim 4 .
15. The double salt according to claim 10 , wherein the chiral resolving agent is as defined in claim 7 .
16. The double salt according to claim 11 , wherein the chiral resolving agent is as defined in claim 6 .
17. The double salt according to claim 11 , wherein the chiral resolving agent is as defined in claim 7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/487,071 US6441178B2 (en) | 1997-01-17 | 2000-01-19 | Resolution of ritalinic acid salt |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB97000912.0 | 1997-01-17 | ||
| GBGB9700912.0A GB9700912D0 (en) | 1997-01-17 | 1997-01-17 | Resolution |
| GB97000912 | 1997-01-17 | ||
| US4125497P | 1997-03-17 | 1997-03-17 | |
| US815298A | 1998-01-16 | 1998-01-16 | |
| US09/487,071 US6441178B2 (en) | 1997-01-17 | 2000-01-19 | Resolution of ritalinic acid salt |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US815298A Continuation | 1997-01-17 | 1998-01-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US20020019535A1 true US20020019535A1 (en) | 2002-02-14 |
| US6441178B2 US6441178B2 (en) | 2002-08-27 |
Family
ID=10806137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/487,071 Expired - Fee Related US6441178B2 (en) | 1997-01-17 | 2000-01-19 | Resolution of ritalinic acid salt |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6441178B2 (en) |
| EP (1) | EP0958281B1 (en) |
| JP (1) | JP2001508791A (en) |
| AT (1) | ATE262510T1 (en) |
| AU (1) | AU5569198A (en) |
| CA (1) | CA2272716C (en) |
| CZ (1) | CZ293045B6 (en) |
| DE (1) | DE69822606T2 (en) |
| DK (1) | DK0958281T3 (en) |
| ES (1) | ES2218799T3 (en) |
| GB (1) | GB9700912D0 (en) |
| HU (1) | HUP0000777A3 (en) |
| NO (1) | NO993517D0 (en) |
| PL (1) | PL189745B1 (en) |
| PT (1) | PT958281E (en) |
| WO (1) | WO1998031668A1 (en) |
| ZA (1) | ZA98374B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040091532A1 (en) * | 1995-12-04 | 2004-05-13 | Mehta Atul M. | Delivery of multiple doses of medications |
| US20060030587A1 (en) * | 1995-12-04 | 2006-02-09 | Celgene Corporation | Method of treating attention deficit disorders with d-threo methylphenidate |
| US20060127421A1 (en) * | 2004-12-09 | 2006-06-15 | Celgene Corporation | Treatment using D-threo methylphenidate |
| US20060142583A1 (en) * | 1997-05-22 | 2006-06-29 | Vikram Khetani | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
| US20060183774A1 (en) * | 1995-12-04 | 2006-08-17 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
| US20090062336A1 (en) * | 2004-04-26 | 2009-03-05 | Celgene Corporation | Methods of Diminishing Co-Abuse Potential |
| 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 |
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| US7247730B2 (en) * | 2003-03-07 | 2007-07-24 | Isp Investments Inc. | Process for the preparation of dexmethylphenidate hydrochloride |
| EP2937336A1 (en) * | 2010-12-17 | 2015-10-28 | Rhodes Technologies | Low-temperature synthesis of methylphenidate hydrochloride |
| US9283214B2 (en) | 2011-03-23 | 2016-03-15 | 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 |
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| 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 |
| US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
| MX357551B (en) | 2011-03-23 | 2018-07-13 | Ironshore Pharmaceuticals & Dev Inc | Methods and compositions for treatment of attention deficit disorder. |
| US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
| US9278928B2 (en) * | 2012-11-29 | 2016-03-08 | Zcl Chemicals Limited | Process for the preparation of d-threo-ritalinic acid salts via novel salts of intermediate thereof |
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| US2957880A (en) * | 1953-12-23 | 1960-10-25 | Ciba Pharm Prod Inc | Process for the conversion of stereoisomers |
| SU466229A1 (en) * | 1973-01-23 | 1975-04-05 | Всесоюзный научно-исследовательский химико-фармацевтический институт им. С.Орджоникидзе | Method for preparing methyl trio-phenyl- (piperidyl-2) -acetic acid hydrochloride |
| US4285964A (en) | 1979-08-30 | 1981-08-25 | Continental Pharma | Salts of (+)-catechine, their preparation and use, and compositions containing these salts |
| US5162344A (en) | 1987-05-04 | 1992-11-10 | Robert Koch | Procaine double salt complexes |
| PT879228E (en) * | 1996-02-02 | 2003-01-31 | Medeva Europ Ltd | PROCESS FOR THE PREPARATION OF D-TREO- (R, R) -METHYLPHENIDATE AND RECYCLING OF UNSAFE BY EPIMERIZATION |
| ES2173422T3 (en) * | 1996-03-08 | 2002-10-16 | Medeva Europ Ltd | DISRECIATION OF TREO-METHYLPHENIDATE. |
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1997
- 1997-01-17 GB GBGB9700912.0A patent/GB9700912D0/en active Pending
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1998
- 1998-01-14 DK DK98900603T patent/DK0958281T3/en active
- 1998-01-14 AU AU55691/98A patent/AU5569198A/en not_active Abandoned
- 1998-01-14 HU HU0000777A patent/HUP0000777A3/en unknown
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- 1998-01-14 WO PCT/GB1998/000112 patent/WO1998031668A1/en active IP Right Grant
- 1998-01-14 ES ES98900603T patent/ES2218799T3/en not_active Expired - Lifetime
- 1998-01-14 JP JP53393298A patent/JP2001508791A/en active Pending
- 1998-01-14 EP EP98900603A patent/EP0958281B1/en not_active Expired - Lifetime
- 1998-01-14 PT PT98900603T patent/PT958281E/en unknown
- 1998-01-14 PL PL98334838A patent/PL189745B1/en not_active IP Right Cessation
- 1998-01-14 CZ CZ19992302A patent/CZ293045B6/en not_active IP Right Cessation
- 1998-01-16 ZA ZA98374A patent/ZA98374B/en unknown
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- 1999-07-16 NO NO993517A patent/NO993517D0/en not_active Application Discontinuation
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090088455A1 (en) * | 1995-12-04 | 2009-04-02 | Celgene Corporation | Chronic, Bolus Adminstration Of D-Threo Methylphenidate |
| US20060030587A1 (en) * | 1995-12-04 | 2006-02-09 | Celgene Corporation | Method of treating attention deficit disorders with d-threo methylphenidate |
| US20060183774A1 (en) * | 1995-12-04 | 2006-08-17 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
| US7115631B2 (en) | 1995-12-04 | 2006-10-03 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
| US7431944B2 (en) | 1995-12-04 | 2008-10-07 | Celgene Corporation | Delivery of multiple doses of medications |
| US20040091532A1 (en) * | 1995-12-04 | 2004-05-13 | Mehta Atul M. | Delivery of multiple doses of medications |
| US20110201645A1 (en) * | 1995-12-04 | 2011-08-18 | Zeitlin Andrew L | Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate |
| US20060142583A1 (en) * | 1997-05-22 | 2006-06-29 | Vikram Khetani | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
| US7459560B2 (en) | 1997-05-22 | 2008-12-02 | Celgene Corporation | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
| US20090062336A1 (en) * | 2004-04-26 | 2009-03-05 | Celgene Corporation | Methods of Diminishing Co-Abuse Potential |
| US20060127421A1 (en) * | 2004-12-09 | 2006-06-15 | Celgene Corporation | Treatment using D-threo methylphenidate |
| US20110118310A1 (en) * | 2004-12-09 | 2011-05-19 | Celgene Corporation | Treatment Using D-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 |
Also Published As
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| CZ293045B6 (en) | 2004-01-14 |
| US6441178B2 (en) | 2002-08-27 |
| AU5569198A (en) | 1998-08-07 |
| GB9700912D0 (en) | 1997-03-05 |
| HUP0000777A2 (en) | 2000-09-28 |
| DE69822606D1 (en) | 2004-04-29 |
| EP0958281B1 (en) | 2004-03-24 |
| CA2272716A1 (en) | 1998-07-23 |
| WO1998031668A1 (en) | 1998-07-23 |
| EP0958281A1 (en) | 1999-11-24 |
| HUP0000777A3 (en) | 2000-10-30 |
| ATE262510T1 (en) | 2004-04-15 |
| ES2218799T3 (en) | 2004-11-16 |
| PL189745B1 (en) | 2005-09-30 |
| PT958281E (en) | 2004-07-30 |
| CA2272716C (en) | 2007-09-18 |
| JP2001508791A (en) | 2001-07-03 |
| ZA98374B (en) | 1999-01-22 |
| PL334838A1 (en) | 2000-03-27 |
| DE69822606T2 (en) | 2004-08-05 |
| CZ230299A3 (en) | 1999-11-17 |
| NO993517L (en) | 1999-07-16 |
| DK0958281T3 (en) | 2004-06-14 |
| NO993517D0 (en) | 1999-07-16 |
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