Petrolite Corporation

Mallinckrodt Specialty Chemicals Company

Mallinckrodt, Inc.

Targacept, Inc.

Mallinckrodt Chemical, Inc.

Attenua, Inc.

Jacob Mathew

J Kendall Killgore

Gary Maurice Dull

Bernardus A Oude Alink

Merouane Bencherif

Anatoly A Mazurov

Lan Miao

Julio A Munoz

Thomas G Braga

Sayed Sadiq Shah

John Genus

Kristen G Jordan

Nikolai Fedorov

Gregory J Gatto

Lisa Benson

Inigo Pfeiffer

Sondra Pfeiffer

Teresa Y Phillips

The present invention relates to (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, novel salt forms thereof, methods for its preparation, novel intermediates, and methods for treating a wide variety of conditions and disorders, including those associated with dysfunction of the central and autonomic nervous systems.

(2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, novel salt forms, and methods of use thereof

Synthetic pathways are disclosed for synthesizing derivatives or analogs of fentanyl. Specifically set out are pathways for synthesizing alfentanil, sufentanil and remifentanil. The disclosed methods require fewer steps and produce a greater yield of product than methods reported in the prior art.

Methods for the synthesis of alfentanil, sufentanil, and remifentanil

Synthetic pathways are disclosed for synthesizing derivatives or analogs of fentanyl. Specifically set out are pathways for synthesizing alfentanil, sufentanil and remifentanil. The disclosed methods require fewer steps and produce a greater yield of product than methods reported in the prior art. The pathways to all these compounds begin with a common pathway of condensing a piperidone with a primary amine so as to form a 4-amino carboxyamino-piperidine, wherein N of said piperidone is a &#x2014;N&#x2014;COO&#x2014;(CH)CH, alkylating an N of said primary amine which was condensed with said piperidone thereby producing an N-alkyl-anilide, and hydrolyzing said &#x2014;COO&#x2014;(CH)3? group of said 4-amino-4-carboxyamino-piperidine following the condensation reaction so as to form a piperidine hydrolysis product. This product can then be convened to remifentanil in a 4 step reaction. Also, this hydrolysis product can be treated with a hydride to yield a 4-hydroxymthyl-piperidine which can be converted to alfentanil in 3 further steps, to sufentanil in 3 more steps, or to a variety of remifentanil analogs in two steps.

Methods for the syntheses of alfentanil, sufentanil and remifentanil

A piperidine derivative such as sufentanil is formed in a process which includes the step of condensing a piperidone with a primary amine so as to form a 4-amino-4-carboxyamino-piperidine.

Preparation of piperidine derivatives

A method for inhibiting corrosion of a metal surface in a liquid medium is described. The method comprises incorporating into the medium a corrosion inhibiting amount of a combination of a surfactant that forms a bilayer on the metal surface in the fluid and a corrosion inhibitor that solubilizes in the medium in the presence of the surfactant. The amount of surfactant is sufficient to produce a bilayer on the metal surface in the medium. The combination is a. an anionic surfactant that forms a bilayer on the metal surface and a cationic corrosion inhibitor; b. a cationic surfactant that forms a bilayer on the metal surface and an anionic corrosion inhibitor; c. an ionic surfactant that forms a bilayer on the metal surface and an ionic corrosion inhibitor having a pendent, generally straight chain hydrocarbon or substituted hydrocarbon moiety of from about 10 to about 18 carbon atoms; or d. an ionic surfactant that forms a bilayer on the metal surface and a non-ionic corrosion inhibitor. Related compositions and methods are also disclosed.

Corrosion inhibition with bilayer-forming surfactants

A method of preparing an .alpha.-d-phenylalkylbenzyl carbinol by the reaction of a phenylbenzyl ketone with an alkali metal enolate of an amide to form an aldol adduct, which is reduced and purified to form an .alpha.-d-phenylalkylbenzyl carbinol, wherein the carbinol so produced possesses analgesic activity. In an embodiment of the invention, a phenylbenzyl ketone is reacted with an alkali metal enolate of an amide to form an aldol adduct, which is reacted with an alkali metal salt of a secondary amine to form a dianion; the dianion is alkylated with an alkyl halide to form an .alpha.-isomer of an aldol adduct, which is reduced and purified to form an .alpha.-d-phenylalkylbenzyl carbinol possessing analgesic activity.

Method of preparing .alpha.-d-phenylalkylbenzyl carbinol

Substantially stereospacific (E)-tetrasubstituted acrylic esters, such as ##STR1## where R is hydrogen alkyl, R.sub.1 is alkyl, aryl or aralkyl, R.sub.2 and R.sub.4 are alkyl, are formed from racemic mixtures of corresponding unsaturated esters and cuprates of the formula (R.sub.3).sub.2 CuX, wherein R.sub.3 is alkyl, aryl or aralkyl, and X is lithium or magnesium halide.

Stereospecific synthesis of tetrasubstituted acrylic esters

In a method for producing 2(R)-2-methyl-3-dimethylamino-propiophenone (d-DAMP), a chiral ester of the formula ##STR1## wherein R is an alkyl of from 1 to about 5 carbon atoms, is provided. The chiral easter of formula (I) is converted into a chiral amino-alcohol of the formula ##STR2## and the chiral amino-alcohol is oxidized so as to form d-DAMP.

Stereospecific synthesis of 2(R)-2-methyl-3-dimethylamino-propiophenone

An alkyl 2-thiosubstituted-3-substituted-2-butenoate ##STR1## is prepared by reacting an alkyl 2-chloro-3-substituted-3-butenoate with a thio compound under phase transfer conditions.

Alkyl-2-thiosubstituted-3-substituted-2-butenoates and their synthesis

2,3,5-trisubstituted-2-cyclopentenones or 2,3-disubstituted-2-cyclopentenones (such as cis-jasmone) are prepared by contacting a 3-chloro-3,4-disubstituted-4-pentene-2-one with a strong base. Methods of preparing the reactants are also disclosed.

Synthesis of 2,3,5-trisubstituted-2-cyclopentenones via base induced

2,3-disubstituted-2-cyclopenenones (such as cisjasmone) are prepared by (a) reacting an alkl 2-chloro-2,3-disubstituted-3-butenoate with a lithiomercaptan compound, (b) subjecting that product to reductive dehydrosulfurization. Methods of preparing the reactants are also disclosed.

Synthesis of 2,3-disubstituted-2-cyclopentenones via

N,3,4-trisubstituted-3-azoline-2-ones (such as N-benzyl-3,4-dimethyl-3-azoline-2-one) are prepared by the reaction of an alkyl 2-chloro-2,3-disubstituted-3-butenoate (such as ethyl 2-chloro-2,3-dimethyl-3-butenoate) with a primary amine (such as benzyl amine). Methods for preparing the precursor esters are also disclosed.

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Fenton, MO, United States of America

Jacob Mathew