US 8,283,472 B2Granted

Synthesis of methylphenidate and analogs thereof

AssigneeMallinckrodt Inc.

InventorsJoseph P. Haar, Jr., Carl J. Schaefer, Charles S. Kuivila

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Abstract

A synthetic process for the preparation of amino acid esters such as methylphenidate and analogs thereof is disclosed. The process involves reacting an amino acid such as α-phenyl-α-(2-piperidinyl)acetic acid or an analog thereof with an alcohol such as methanol in the presence of an acid and a water sequestrant such as trimethyl orthoacetate. In some embodiments, the water sequestrant is added to the reaction mixture after an initial period of esterification and then the reaction is allowed to continue. The α-phenyl-α-(2-piperidinyl)acetic acid methyl ester or analog thereof is then isolated from the reaction mixture. In one variation of the process, the supernatant liquid may be recycled in subsequent runs to increase yield and product purity.

Claims20

Dependent claims

A synthetic esterification process comprising:

(i) reacting
(a) an amino acid of Formula I:
wherein Ra is a substituent at one or more of carbons 2, 3, 4, 5 and 6 of the phenyl ring, wherein the substituent is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, halogen and —NRmRn, wherein Rm and Rn are independently selected from the group consisting of hydrogen, alkyl, haloalkyl and alkoxyalkyl;
wherein Rb is a substituent at one or more of carbons 7, 8, 9, 10 and 11 of the piperidine ring, wherein the substituent is independently selected from the group consisting of hydrogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and halogen;
and
wherein Rc is selected from the group consisting of hydrogen, alkyl, haloalkyl, aralkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, and
wherein Rt is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aralalkoxy and aralkyl;
with
(b) an alcohol of formula Ry—OH, wherein Ry is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
in the presence of
(c) an acid;
and
(d) a water sequestrant
to produce a reaction mixture containing an amino acid ester of Formula II
and
(ii) isolating the amino acid ester of Formula II or a pharmaceutically acceptable salt thereof.

13 more elements

Dependencies are inferred from the claim text.