- An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride
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The present work describes an efficient and commercially viable process for the synthesis of dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with ~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also described in this report.
- Xing, Long-Xuan,Shen, Cheng-Wu,Sun, Yuan-Yuan,Huang, Lei,Zheng, Yong-Yong,Li, Jian-Qi
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p. 1298 - 1303
(2017/03/27)
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- Dexmethylphenidate: An efficient process for the racemization of Unwanted (2 S,2 S or l - Threo)-α-Phenyl-α-(2-piperidyl)acetamide
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(2R,2 R)-d-threo-α-Phenyl-α-(2-piperidyl)acetamide (3), an advanced intermediate for dexmethylphenidate hydrochloride synthesis, is prepared by the resolution of dl-threo-α-phenyl-α-(2-piperidyl) acetamide (2) with dibenzoyl-d-tartaric acid in isopropanol with % yield and 99% ee. Although this process is efficient, there is a need to recycle the unwanted l-threo-amide and uncrystallized d-threo- amide from the mother liquor. The purpose of this study is 2-fold, first being the pollution issue to discard large amounts of unwanted isomer and the second to reduce the cost of (1). This aspect of recovery of unwanted isomer 4 formed the basic objective of this study. We have developed a new, simple, and cost-effective process for the racemization in which 4 was treated with potassium carbonate and N-chlorosuccinimide in DMF followed by treatment with DBU to afford the olefinic intermediate (5). Subsequent hydrogenation of the double bond provided dl-erythro-α-phenyl-α-(2-piperidyl)acetamide (6); the latter intermediate has already been converted into 1.
- Chavan, Anil B.,Gundecha, Sachin S.,Kadam, Pramod N.,Maikap, Golak C.,Gurjar, Mukund K.
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experimental part
p. 1473 - 1475
(2011/09/20)
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- A PROCESS FOR THE PREPARATION OF ALPHA-ARYL-ALPHA-PIPERID-2-YL-ACETAMIDES AND THE ACID HYDROLYSIS THEREOF
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A process for the preparation of -aryl--piperid-2-yl-acetamides of formula (I) in which Ar is as defined in the disclosure, by catalytic reduction of α-aryl-α-pyridin-2-yl-acetamides (II) with rhodium catalysts. Acetamides of formula (II) can subsequently by hydrolysed to the corresponding arylacetic acids, e. g. ritalinic acid, a direct precursor of methylphenidate.
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Page/Page column 4
(2008/06/13)
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- An improved manufacturing process for methylphenidate and intermediates thereof
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The present invention discloses selective and complete reduction of pyridine ring in a biaryl system comprising α-substituted or non-substituted benzene ringand relates more specifically, not exclusively, for the manufacture of methylphenidate, which is used for treatment of Attention Deficit Hyperactive Disorder (ADHD) and also acts as central nervous system stimulant, by using palladium/C in a solvent such as C1-C4 alcohols in presence of molar quantities of organic and/or inorganic acids.
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Page/Page column 4
(2008/06/13)
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- Manufacturing process for methyl phenidate and intermediates thereof
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The present invention discloses selective and complete reduction of pyridine ring in a biaryl system comprising ∝-substituted or nonsubstituted benzene ring and relates more specifically, not exclusively, for the manufacture of methylphenidate, which is used for treatment of Attention Deficit Hyperactive Disorder (ADHD) and also acts as central nervous system stimulant, by using palladium/C in a solvent such as C1-C4 alcohols in presence of molar quantities of organic and/or inorganic acids.
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Page/Page column 3
(2008/06/13)
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- PROCESSES AND INTERMEDIATES FOR PREPARING 2-SUBSTITUTED PIPERIDINE STEREOISOMERS
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A process for preparing d-threo methyl ±- piperid-2-ylarylacetates of formula III: wherein R 1 is aryl having 6 to 28 carbon atoms, comprising the steps of: reacting a pyridine having formula I: wherein R 1 is aryl having 6 to 28 carbon atoms with hydrogen in an alkanoic acid having 1 to 10 carbon atoms and in the presence of a catalyst to provide a mixture of threo and erythro piperidine stereoisomers having formulas IIa-d: €?€?€? adding an alkyl alkanoate having 2 to 20 carbon atoms to said mixture, thereby precipitating alkanoate salts of said erythro stereoisomers preferentially with respect to alkanoate salts of said threo stereoisomers; reacting said erythro alkanoate salts with aqueous base to form said erythro stereoisomers; reacting said erythro stereoisomers with an acid resolving agent in an alkyl alcohol having 1 to 5 carbon atoms, thereby forming acid salts of said 1-erythro stereoisomers preferentially with respect to said d-erythro stereoisomers; reacting said 1-erythro acid salts with aqueous base to form said 1-erythro piperidine; reacting said 1-erythro piperidine with an alkali metal alkoxide having one to 10 carbon atoms in organic solvent, whereby forming said d-threo piperidine, and converting said d-threo piperidine to said d-threo methyl ±- piperid -2- ylarylacetate.
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Page/Page column 5
(2008/06/13)
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- Synthesis and molecular structure of novel 4-aryloctahydropyrido-[1,2-c]pyrimidine derivatives
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A series of new 4-aryloctahydropyrido[1,2-c]pyrimidine-1,3-diones 6a,b,d-h and j were synthesized by intramolecular cyclization of α-aryl-α(1-ethoxycarbonyl-2-piperidyl)-acetamide derivatives 5a,b,d-h and j. The structures of compounds were determined by 1H and 13C nmr spectroscopy. Nmr and X-ray diffraction data indicate that the configuration at the C4, C4a stereocenters constitute RR and SS pair.
- Herold, Franciszek,Kleps, Jerzy,Anulewicz-Ostrowska, Romana,Szczesna, Beata
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p. 773 - 782
(2007/10/03)
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- Processes and intermediates for resolving piperidyl acetamide stereoisomers
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Processes and intermediates for preparing 2-substituted piperidines such as 2-substituted d-threo piperidines are provided, including processes and intermediates for resolution of piperidyl acetamide stereoisomers.
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- Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs
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As part of a program, to develop medications which can block the binding of cocaine to the dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted methylphenidate derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Synthesis was accomplished by alkylation of 2-bromopyridine with anions derived from various substituted phenylacetonitriles. In most cases, erythro compounds were markedly less potent than the corresponding (±)-threo-methylphenidate (TMP; Ritalin) derivatives. The ortho-substituted compounds were much less potent than the corresponding meta- and/or para-substituted derivatives. The most potent compound against [3H]WIN 35,428 binding, m-bromo-TMP, was 20-fold more potent than the parent compound, whereas the most potent compound against [3H]dopamine uptake, m,p-dichloro-TMP, was 32-fold more potent. Threo derivatives with m-or p-halo substituents were more potent than TMP, while electron-donating substituants caused little change or a small loss of potency. All of the derivatives had Hill coefficients approaching unity, except m,p-dichloro-TMP, which had an nH of 2.0. Although the potency of the (±)-methylphenidate derivatives in the two assays was highly correlated (R2 = 0.986), the compounds m-chloro-, m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [3H]-WIN 35,428 binding than [3H]dopamine uptake (cocaine has a ratio of 2.3). These and other compounds may be promising candidates for further testing as potential partial agonists or antagonists of cocaine.
- Deutsch, Howard M.,Shi, Qing,Gruszecka-Kowalik, Ewa,Schwer, Margaret M.
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p. 1201 - 1209
(2007/10/03)
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