Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1998-09-25
2000-02-29
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
558390, 560 27, 564164, C07C22900
Patent
active
06031124&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the synthesis of methylphenidate by cyclisation of new 7-amino-2-heptenoates.
BACKGROUND OF THE INVENTION
Methylphenidate has utility as a therapeutic agent, e.g. in the treatment of attention-deficient hyperactivity disorder. It was first prepared as a mixture of the erythro and threo racemates. U.S. Pat. No. 2,957,880 discloses its synthesis and also studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereomer.
JP-A-53007627 discloses the formula alkyl. This structure is indicated as suitable for cyclisation to 1-(1-phenylethyl)-2-hydroxy-5-piperidinone, en route to antihistaminic agents.
No cyclisation is demonstrated. Further, the elemental analysis of the compound that is made, consistent with the intended product, indicates that it is actually of the formula cyclisation.
Knouzi et al, Tet. Lett. 28(16):1757-60 (1987), disclose cyclisation, again by Michael addition, of 7-arnino-2-heptenoates of the formula compounds, were obtained with good diastereoselectivity, except for the given compound when R" is CH.sub.3.
SUMMARY OF THE INVENTION
The present invention is based on the realisation that compounds of formula I group, or Y.sup.1 and Y.sup.2 together are a removable divalent blocking group, and X is COOCH.sub.3 or a group convertible thereto, are novel intermediates that provide the basis of a new synthesis of methylphenidate. Further, cyclisation by Michael addition proceeds substantially only on one of the two geometric isomers. Thus, contrary to the most closely analogous situation in the prior art, effective and useful diastereoselectivity is found.
Therefore, according to a further aspect of this invention, compounds of formula I when Y.sup.2 is H can be converted to methyiphenidate by Michael addition, using a base such as lithium diethylamine, removing any blocking group represented by Y.sup.1, and converting X to COOCH.sub.3, if necessary.
According to yet another aspect of the invention, compounds of formula I may be prepared by a Horner-Wadsworth-Emmons reaction of corresponding compounds of the formulae Ph--CHX--PO(Oalk).sub.2 and Y.sup.1 Y.sup.2 N--(CH.sub.2).sub.4 --CHO, wherein Y.sup.2 is a blocking group; and, if desired, removing the blocking group to give the product in which Y.sup.2 is H.
DESCRIPTION OF THE INVENTION
X is preferably COOCH.sub.3. Alternatively, it may be CN, CONH.sub.2 or COOR.sup.1, R.sup.1 being H or alkyl or aralkyl of up to 10 C atoms. Other groups X that can readily be converted to COOCH.sub.3, and methods of conversion, will be readily apparent to one of ordinary skill in the art.
Y.sup.1 and Y.sup.2 may each be H. Either or each, or the two together, may also be a blocking group. Groups that can readily be introduced onto a N atom, and readily removed after another part of the molecule has undergone reaction, are well known to those of ordinary skill in the art. For example, reference may be made to T. W. Greene et al, "Protecting Groups in Organic Synthesis", 2nd ed. Wiley-Interscience, New York (1991). A particular example of a suitable blocking group is t-butyloxycarbonyl (Boc). An example of Y.sup.1 and Y.sup.2 together with N is phthalimido.
In certain circumstances, it may be preferred that Y.sup.1 is a chiral auxiliary, in single enantiomer form. A preferred example is 1-phenylethyl, which may be introduced using, say, .alpha.-methylbenzylaiine (.alpha.-MBA), and removed by hydrogenation. The use of a chiral auxiliary may assist control of absolute and/or relative stereochemistry. Either enantiomer may be used, depending on the desired product, and this may readily be determined by experiment. Any erythro diastereoisomer formed by cyclisation may be subjected to epimerisation at the benzylic position to give optically-enriched threo methylphenidate or a derivative thereof.
Each of the reactions described herein may be conducted by generally known methodology, and any variations that may be necessary for optimisation can readily be determi
REFERENCES:
patent: 2957880 (1960-10-01), Rometsch
Knouzi, N. et al. (1987) Intramolecular Cyclization of .omega.-Primary Amino Electrophilic Olefins to Functionalized Pyrrolidines and Piperidines. Tetrahedron Letters 28(16): 1757-1760.
Fox Martin Edward
Paul Jane Marie
Killos Paul J.
Medeva Europe Limited
Oh Taylor V.
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