MXPA98007266A - Treo-metilfenid resolution - Google Patents
Treo-metilfenid resolutionInfo
- Publication number
- MXPA98007266A MXPA98007266A MXPA/A/1998/007266A MX9807266A MXPA98007266A MX PA98007266 A MXPA98007266 A MX PA98007266A MX 9807266 A MX9807266 A MX 9807266A MX PA98007266 A MXPA98007266 A MX PA98007266A
- Authority
- MX
- Mexico
- Prior art keywords
- resolution
- methylphenidate
- threo
- treo
- metilfenid
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 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 4
- 229960001042 dexmethylphenidate Drugs 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 abstract description 2
- 229960001344 methylphenidate Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- -1 (-) - methoxyacetyl Chemical group 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-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
- 239000004305 biphenyl Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
A method for preparing the substantially individual enantiomer d-threo-methylphenidate is described, proceeds through means of a classical salt resolution using (-) - methoxyacetic acid.
Description
TREO-METHYLPHENIDATE RESOLUTION DESCRIPTION OF THE INVENTION This invention relates to the resolution of threo-methylphenidate through the crystallization of diastereomeric salts. The methylphenidate was first prepared as a mixture of ether and threo racemates. US-A-2957880 describes studies on the two racemic mixtures, which reveal that the therapeutic activity resides in. the threo diastereomer. Resolution of treormethylphenidate can be achieved by using the expensive resolution agent, with 1, 1'-diacid phosphate, 2'-2'-biphenyl, a first procedure reported by Patric et al (The Journal of Eharmacology and Experimental Therapeutics, 241: 152- 158 (1987)), and subsequently used by other workers in the field (eg, Aoyama et al., Journal of Chromatography, 494: 420 (1989)). This was perceived as a more efficient process than the method described in US-A2957880, where the corresponding amide of er-methyl-methylphenidate (ie, R-CONR, instead of R-C0N-Me) was resolved with tartaric acid , before hydrolysis with amide and equilibrium in the benzylic center, followed by the esterification of the resulting acid.
An improved resolution procedure is described in PCT / GB97 / 00185. Said resolution can be combined, with the racemization described in PCT / GB97 / 00281_. This invention is based on the discovery that racemic threo-methylphenidate can be resolved using very expensive (-) -methoxyacetic acid. The process of this invention can be carried out under conditions that are generally known to those skilled in the art of classical salt resolution procedures. For example, a mixture of treo-. Free base methylphenidate and one molar equivalent of _ (-) - methoxyacetyl acid in an inert organic solvent is heated and allowed to cool; the resulting precipitate is filtered, washed with an appropriate solvent and dried to directly yield a salt rich in 98% ee of d-threo-methylphenidate. This is a huge improvement in the method of the literature using phosphate 2-2 '- 1-1'-hydrophilic acid, described by Patpck et al., Supra, where the first crystallization gave a salt corresponding to 85-90 ^ of the . material, and additional recrystallization of this material was necessary to increase the ee., to 95-97%. The last level of optical purity was achieved in the present invention in a crystallization, with a higher total yield. The method of this invention, therefore, is more efficient and more economical than that described by Patrick et al.
The following example illustrates the resolution of threo-methylphenidate using [-] -methoxyacetic acid. EXAMPLE dJ-Threo-methylphenidate (1.0 g, 3.7 mmol) was suspended in water (20 ml) and treated with a caustic solution. The released free base was extracted with MTBE (3x25ml), dried over MgSO (, and evaporated to a light oil.) This was dissolved in IPA (15 ml) and heated to 60 ° C, (-) - acid was added. methoxyacetic (0.79 g, 3.79 mmole) in IPA (5 ml) The heating was continued for a further 30 minutes and the mixture was gradually cooled to 10 ° C. The resulting white crystalline product was filtered, washed with cold IPA and dried (0.85 g, 47% by weight, corresponding to 98? ee of d-threo-methylphenidate, as determined by chiral CLAP after salt distillation).
Claims (1)
1. A process for preparing the substantially individual enantiomer d-threo-methylphenidate which proceeds through a classical salt resolution using acid. { -) -methoxyacetic.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9604943.2A GB9604943D0 (en) | 1996-03-08 | 1996-03-08 | Resolution |
| GB9604943.2 | 1996-03-08 | ||
| US1698696P | 1996-05-07 | 1996-05-07 | |
| US016986 | 1996-05-07 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| MX9807266A MX9807266A (en) | 1999-08-31 |
| MXPA98007266A true MXPA98007266A (en) | 1999-10-14 |
| MX202728B MX202728B (en) | 2001-06-29 |
Family
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