Patents by Inventor Thomas B. K. Lee
Thomas B. K. Lee has filed for patents to protect the following inventions. This listing includes patent applications that are pending as well as patents that have already been granted by the United States Patent and Trademark Office (USPTO).
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Patent number: 5734062Abstract: This invention relates to a process for the preparation of a product of the formula ##STR1## wherein R is loweralkyl; R.sub.1 is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; Rs is loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) ##STR2## wherein Y is hydrogen or loweralkyl and Z is hydrogen, loweralkyl, halogen, loweralkoxy or hydroxy; X is loweralkyl, loweralkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which process comprises(a) contacting a compound of formula (II) as defined herein with fortified hydrogen bromide to afford a compound of formula (III) as defined herein; contacting the reaction mixture containing a compound of formula (III) with either (1) an isocyanate of formula R.sub.Type: GrantFiled: May 20, 1997Date of Patent: March 31, 1998Assignee: Hoechst Marion Roussel, Inc.Inventors: Thomas B. K. Lee, Zhongli Gao
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Patent number: 5677457Abstract: The present invention relates to a novel process for the preparation of physostigmine carbamate derivatives and to pharmaceutically acceptable salts thereof. The present invention further relates to a novel process for the preparation of eseroline derivatives and to pharmaceutically acceptable salts thereof.Type: GrantFiled: December 19, 1996Date of Patent: October 14, 1997Assignee: Hoechst Marion Roussel, Inc.Inventors: Thomas B. K. Lee, Zhongli Gao, Barbara S. Rauckman
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Patent number: 5665880Abstract: This invention relates to a process for the preparation of a product of the formula ##STR1## wherein R is loweralkyl; R.sub.1, is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralyl; R.sub.2 is lower alkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) ##STR2## wherein Y is hydrogen or loweralkyl and Z is hydrogen, loweralkyl, halogen, loweralkoxy or hydroxy; X is loweralkyl, loweralkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which process comprises(a) contacting a compound of formula (II) as defined herein with fortified hydrogen bromide to afford a compound of formula (III) as defined herein; contacting the reaction mixture containing a compound of formula (III) with either (1) an isocyanate of formula R.sub.Type: GrantFiled: October 31, 1996Date of Patent: September 9, 1997Assignee: Hoechst Marion Roussel, Inc.Inventors: Thomas B. K. Lee, Zhongli Gao
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Process for the enantioselective synthesis of intermediates used in the preparation of physostigmine
Patent number: 5521320Abstract: This invention relates to a process of obtaining optically pure enantiomers of an alkylated oxindole selected from ##STR1## where R is methyl, ethyl or benzyl.Type: GrantFiled: May 27, 1993Date of Patent: May 28, 1996Assignee: Hoechst-Roussel Pharmaceuticals IncorporatedInventors: Thomas B. K. Lee, George S. K. Wong -
Patent number: 5498726Abstract: This application relates to a new process for the preparation of a product of the formula ##STR1## wherein R, R.sup.1, R.sup.2, X and m are as defined within, which process comprises preparing treating a compound such as physostigmine to form eseroline which is then treated with an appropriate compound or its equivalent. Acetic acid is added to the reaction mixture after the formation of eseroline.Type: GrantFiled: March 22, 1994Date of Patent: March 12, 1996Assignee: Hoechst-Roussel Pharmaceuticals IncorporatedInventors: George E. Lee, Thomas B. K. Lee, Donna M. Borek
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Patent number: 5489681Abstract: A compound of the formula ##STR1## is prepared by reacting an N-acylated-o-toluidine of the formula ##STR2## with n-alkyllithium to form a dilithio intermediate of the formula ##STR3## which can then be quenched with N-benzylidenemethylamine to fore compound II. Hydrolysis of compound(II) yields the free base ##STR4## or its salt, which can be cyclized to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or its physiologically acceptable salts, which are useful as pharmacological agents.Type: GrantFiled: September 9, 1994Date of Patent: February 6, 1996Assignee: Hoeschst-Roussel Pharmaceuticals, Inc.Inventors: Thomas B. K. Lee, George E. Lee
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Patent number: 5455354Abstract: This invention relates to a process for the preparation of a product of the formula ##STR1## wherein R, R.sup.1, R.sup.2, X and m are defined within which process comprises(a) contacting a compound of Formula II ##STR2## wherein R.sup.3 is loweralkyl, with a reagent selective from the group consisting of aluminum chloride, hydrobromic acid and boron tribromide followed by tartaric acid to afford a compound of Formula III ##STR3## wherein R, X and m are as defined above; (b) contacting the reaction mixture containing compound of Formula IV ##STR4## wherein R.sup.4 is hydrogen or loweralkyl in the presence of a carboxylic acid of the formulaR.sup.5 COOHwherein R.sup.5 is loweralkyl to afford a compound of formula V ##STR5## wherein R, R.sup.4, X and m are as above; contacting the reaction mixture containing the compound of Formula V obtained in step(b) with a compound of the formulaR.sup.1 R.sup.2 NHwherein R.sup.1 and R.sup.2 are as above; and isolating the product of Formula I.Type: GrantFiled: February 17, 1994Date of Patent: October 3, 1995Assignee: Hoechst-Roussel Pharmaceuticals IncorporatedInventors: George S. K. Wong, Thomas B. K. Lee, Franz J. Weiberth
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Patent number: 5387695Abstract: A process for chemically resolving a mixture of enantiomers of primary amines, such as enantiomers of 1,3-dimethyl-5-methoxyoxindolylethylamine, provides one of the enantiomers in the form of a tartaric acid salt. In carrying out the process, an enantiomeric mixture is contacted with a chiral acid in an amount sufficient to preferentially precipitate a salt of the chiral acid and one of the enantiomers. The resulting precipitate can then be recovered. The chiral acid is selected from the group consisting of dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, ditoluoyl-D-tartaric acid, and ditoluoyl-L-tartaric acid. The precipitates can be used in the synthesis of stereospecific forms of physostigmine.Type: GrantFiled: February 17, 1993Date of Patent: February 7, 1995Assignee: Hoechst-Roussel Pharmaceuticals, Inc.Inventors: Thomas B. K. Lee, George S. K. Wong
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Patent number: 5349086Abstract: A compound of the formula ##STR1## is prepared by reacting an N-acylated-o-toluidine of the formula ##STR2## with n-alkyllithium to form a dilithio intermediate of the formula ##STR3## which can then be quenched with N-benzylidenemethylamine to form compound II. Hydrolysis of compound(II) yields the free base ##STR4## or its salt, which can be cyclized to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or its physiologically acceptable salts, which are useful as pharmacological agents.Type: GrantFiled: November 23, 1992Date of Patent: September 20, 1994Assignee: Hoechst-Roussel Pharmaceuticals, Inc.Inventors: Thomas B. K. Lee, George E. Lee
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Patent number: 5302721Abstract: This application relates to a new process for the preparation of a product of the formula ##STR1## wherein R is loweralkyl;R.sup.1 is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl;R.sup.2 is loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; orR.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached from a 3,4-dihydro-2H(1H)-isoquinoline group;X is loweralkyl, loweralkoxy, halogen or trifluoromethyl; andm is 0, 1 or 2;which process comprises(a) contacting a compound of formula II ##STR2## wherein R, X and m are as defined above and R.sup.3 is loweralkyl, with aluminum chloride followed by tartaric acidto afford a compound of formula III ##STR3## wherein R, X and m are as defined above; (b) contacting the reaction mixture containing the compound of Formula III either(1) with an isocyanate of the formula R.sup.1 NCO and obtaining a product of the formula I wherein R.sup.Type: GrantFiled: July 21, 1992Date of Patent: April 12, 1994Assignee: Hoechst-Roussel Pharmaceuticals IncorporatedInventors: George S. K. Wong, Thomas B. K. Lee, Franz J. Weiberth
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Process for the enantioselective synthesis of intermediates used in the preparation of physostigmine
Patent number: 5274117Abstract: A process for the stereoselective synthesis of [R]- and [S]-2,3-dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitriles comprises reacting racemic and 5-alkoxy-substituted (.+-.)-1,3-dimethyloxindoles with a halogenated acetonitrile in the presence of a substituted N-benzyl cinchoninium, quinidinium, cinchonidinium, or quininium catalyst. The resulting alkylated oxindoles can be converted to primary amines by catalytic reduction in the presence of hydrogen gas. One of the primary amines, such as enantiomers of 3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one, can be enriched by contact with a chiral tartaric acid in an amount sufficient to preferentially precipitate a salt of the chiral acid and one of the enantiomers. The product can be used in the synthesis of stereospecific forms of physostigmine and related compounds having pharmaceutical activity.Type: GrantFiled: February 12, 1992Date of Patent: December 28, 1993Assignee: Hoechst-Roussel Pharmaceuticals, Inc.Inventors: Thomas B. K. Lee, George S. K. Wong -
Patent number: 5155226Abstract: A method of preparing 9-amino-1,2,3,4-tetrahydroacridine by the reaction of 2-aminobenzonitrile and cyclohexanone with p-toluenesulfonic acid monohydrate in xylenes is disclosed.Type: GrantFiled: February 19, 1991Date of Patent: October 13, 1992Assignee: Hoechst-Roussel Pharmaceuticals IncorporatedInventors: Thomas B. K. Lee, Keith E. Goehring
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Patent number: 5053513Abstract: A method of reducing a carbonyl containing acridine of the formula ##STR1## where n is 1, 2 or 3; X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, trifluoromethyl, or NR.sub.3 R.sub.4 where R.sub.3 and R.sub.4 are independently hydrogen or loweralkyl; R is hydrogen or loweralkyl and R.sub.1 is hydrogen, loweralkyl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, furylloweralkyl, thienylloweralkyl, oxygen-bridged arylloweralkyl, oxygen-bridged diarylloweralkyl, oxygen-bridged furylloweralkyl or oxygen-bridged thienylloweralkyl, is disclosed.Type: GrantFiled: March 29, 1990Date of Patent: October 1, 1991Assignee: Hoechst-Roussel Pharmaceuticals IncorporatedInventors: Thomas B. K. Lee, George E. Lee, George S. K. Wong, Donna M. Borek, Keith E. Goehring
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Patent number: 4709093Abstract: A compound of the formula ##STR1## is prepared by reacting an N-acylated-o-toluidine of the formula ##STR2## with n-alkyllithium to form a dilithio intermediate of the formula ##STR3## which can then be quenched with N-benzylidenemethylamine to form compound II. Hydrolysis of compound(II)yields the free base ##STR4## or its salt, which can be cyclized to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or its physiologically acceptable salts, which are useful as pharmacological agents.Type: GrantFiled: July 23, 1985Date of Patent: November 24, 1987Assignee: Hoechst-Roussel Pharmaceuticals Inc.Inventors: Thomas B. K. Lee, George E. Lee
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Patent number: 4579981Abstract: An improved process for the preparation of 2-chloro-1,3-dimethoxybenzene involving the reaction of [2,6-dimethoxyphenyl]lithium with chlorinating agents is disclosed. 2-Chloro-1,3-dimethoxybenzene is useful as a starting material for the synthesis of pharmacologically valuable 1,2-benzisoxazoloxyacetic acids.Type: GrantFiled: August 13, 1984Date of Patent: April 1, 1986Assignee: Hoechst-Roussel Pharmaceuticals Inc.Inventors: Gregory M. Shutske, Thomas B. K. Lee, Gregory M. Jobin
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Patent number: 4496732Abstract: A stereoselective reduction of 2- or 3-substituted 4-piperidones of the formula ##STR1## where R.sub.1 is hydrogen, loweralkyl or benzyl and R.sub.2 is methyl or ethyl, to the di-equatorial isomer of the corresponding 4-piperidinol is described. Said reduction is conducted by use of sodium borohydride in a protic solvent medium at a temperature substantially lower than ambient temperature in the presence of an effective amount of an inorganic acid. Under favorable reaction conditions, the stereoselectivity of the reduction is so high that simple crystallization of the reaction product affords the pure isomer in a commercially acceptable and advantageous process.Type: GrantFiled: March 14, 1983Date of Patent: January 29, 1985Assignee: Hoechst-Roussel Pharmaceuticals Inc.Inventors: George E. Lee, Thomas B. K. Lee
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Patent number: 4461728Abstract: The invention relates to compounds of the formula ##STR1## where Y is --OH; halogen; ##STR2## where R.sub.1 is a straight chain or branched chain alkyl group having 1 to 5 carbon atoms, or aryl; and R.sub.2 is --C(CH.sub.3).sub.3 or --O--C(CH.sub.3).sub.3. Processes for preparing the compounds are provided. The compounds are useful as intermediates in the preparation of 4-phenyl-1,3-benzodiazepins, which exhibit activity as antidepressants, analgetics and anticonvulsants.Type: GrantFiled: November 12, 1982Date of Patent: July 24, 1984Assignee: Hoechst Roussel Pharmaceuticals Inc.Inventors: Thomas B. K. Lee, George E. Lee
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Patent number: 4417063Abstract: A method for the preparation of 6,11-dihydro-11-oxodibenz[b,e]oxepin-acetic acids having pharmaceutical activity is disclosed. Compounds represented by the formula: ##STR1## wherein R is OH or Cl are provided as intermediates. An aldehyde of the formula: ##STR2## wherein R.sub.1 is a lower alkyl, e.g., 1 to 4 carbon atoms, is reacted with chloroform and aqueous base to form an .alpha.-hydroxy dicarboxylic acid. Alternatively, the aldehyde can be converted to the corresponding cyanohydrin, which is then converted to the corresponding .alpha.-hydroxy dicarboxylic acid. The .alpha.-hydroxy dicarboxylic acid can also be prepared from reaction of a halogenated toluate of the formula: ##STR3## wherein X is Cl or Br with mandelic acid or a derivative thereof of the formula: ##STR4## wherein R.sub.3 and R.sub.4 are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms. The .alpha.-hydroxy dicarboxylic acid is cyclized and then converted to the oxepin acetic acid by reduction. Alternatively, the .Type: GrantFiled: May 18, 1981Date of Patent: November 22, 1983Assignee: Hoechst-Roussel Pharmaceuticals Inc.Inventors: Thomas B. K. Lee, George E. Lee, Gregory M. Jobin
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Patent number: 4374067Abstract: The invention relates to compounds of the formula ##STR1## where Y is --OH; halogen; ##STR2## R.sub.1 SO.sub.3 --, where R.sub.1 is a straight chain or branched chain alkyl group having 1 to 5 carbon atoms, or aryl; and R.sub.2 is --C(CH.sub.3).sub.3 or --O--C(CH.sub.3).sub.3. Processes for preparing the compounds are provided. The compounds are useful as intermediates in the preparation of 4-phenyl-1,3-benzodiazepins, which exhibit activity as antidepressants, analgetics and anticonvulsants.Type: GrantFiled: December 23, 1981Date of Patent: February 15, 1983Assignee: Hoechst-Roussel Pharmaceuticals, Inc.Inventors: Thomas B. K. Lee, George E. Lee
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Patent number: 4304941Abstract: A method of preparing substituted acylbenzenes is disclosed. The method comprises reacting selected acylhalides or equivalents with a selected poly-substituted benzene in the presence of an acylating catalyst comprising a clay.Type: GrantFiled: August 1, 1980Date of Patent: December 8, 1981Assignee: Hoechst Roussel Pharmaceuticals, Inc.Inventors: Thomas B. K. Lee, Gregory M. Jobin