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1.发明公开
公开(公告)号：EP0828704A1
公开(公告)日：1998-03-18
申请号：EP96913186.0
申请日：1996-04-26
CPC分类号： C07C227/32 , C07C211/27 , C07C229/08 , C07C233/05
摘要： The present invention provides a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid which comprises condensing isovaleraldehyde with an alkyl cyanoacetate to form a 2-cyano-5-methylhex-2-enoic acid alkyl ester; reacting the 2-cyano-5-methylhex-2-enoic acid alkyl ester with a dialkyl malonate to form 3-isobutylglutaric acid; forming the anhydride of 3-isobutylglutaric acid; reacting the anhydride with ammonia to form (±)-3-(carbamoylmethyl)-5-methylhexanoic acid; reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid with (R)-(+)-α-phenylethylamine to obtain the (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid; combining the salt with an acid to obtain (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid; and reacting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with a Hofmann reagent to obtain (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
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2.发明授权METHOD OF MAKING (1S, 4R)-1-AZABICYCLO 2.2.1]HEPTAN-3-ONE AND (1R, 4S), 1-AZABICYCLO 2.2.1]HEPTAN-3-ONE 失效用于生产（1S，4R）-1-氮杂双环[2.2.1]庚烷-3- ON（1R，4S）-1-氮杂双环[2.2.1]庚烷-3-酮
公开(公告)号：EP0968212B1
公开(公告)日：2002-04-17
申请号：EP98903712.2
申请日：1998-01-27
IPC分类号： C07D487/08
CPC分类号： C07D487/08
摘要： Racemic (+/-)-1-azabicyclo[2.2.1]heptan-3-one may be efficiently resolved into its (1S, 4R)- and (1R, 4S)-1-azabicyclo[2.2.1]heptan-3-one isomers by formation of di-p-toluoyl hemitartrate salts by combination with di-p-toluoyl-L-tartaric acid and di-p-toluoyl-D-tartaric acid, respectively. Selective crystallization using one of the di-p-toluoyltartaric acids in less that stoichiometric amount in a suitable solvent mixture allows isolation of the desired isomer as its respective di-p-toluoyl hemitartrate in high isomeric purity. The isolated hemitartrates are storage stable and may be used as such in the preparation of pharmaceuticals and other biologically active compounds, or may be used to provide the free base of the respective 1-azabicyclo[2.2.1]heptan-3-one isomer.
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3.发明公开METHOD OF MAKING (1S, 4R)-1-AZABICYCLO 2.2.1]HEPTAN-3-ONE AND (1R, 4S), 1-AZABICYCLO 2.2.1]HEPTAN-3-ONE 失效用于生产（1S，4R）-1-氮杂双环[2.2.1]庚烷-3- ON（1R，4S）-1-氮杂双环[2.2.1]庚烷-3-酮
公开(公告)号：EP0968212A1
公开(公告)日：2000-01-05
申请号：EP98903712.2
申请日：1998-01-27
IPC分类号： C07D487/08
CPC分类号： C07D487/08
摘要： Racemic (+/-)-1-azabicyclo[2.2.1]heptan-3-one may be efficiently resolved into its (1S, 4R)- and (1R, 4S)-1-azabicyclo[2.2.1]heptan-3-one isomers by formation of di-p-toluoyl hemitartrate salts by combination with di-p-toluoyl-L-tartaric acid and di-p-toluoyl-D-tartaric acid, respectively. Selective crystallization using one of the di-p-toluoyltartaric acids in less that stoichiometric amount in a suitable solvent mixture allows isolation of the desired isomer as its respective di-p-toluoyl hemitartrate in high isomeric purity. The isolated hemitartrates are storage stable and may be used as such in the preparation of pharmaceuticals and other biologically active compounds, or may be used to provide the free base of the respective 1-azabicyclo[2.2.1]heptan-3-one isomer.
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4.发明授权
公开(公告)号：EP0828704B1
公开(公告)日：2002-03-13
申请号：EP96913186.1
申请日：1996-04-26
IPC分类号： C07C227/32 , C07C229/08 , C07C233/05
CPC分类号： C07C227/32 , C07C211/27 , C07C229/08 , C07C233/05
摘要： The present invention provides a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid which comprises condensing isovaleraldehyde with an alkyl cyanoacetate to form a 2-cyano-5-methylhex-2-enoic acid alkyl ester; reacting the 2-cyano-5-methylhex-2-enoic acid alkyl ester with a dialkyl malonate to form 3-isobutylglutaric acid; forming the anhydride of 3-isobutylglutaric acid; reacting the anhydride with ammonia to form (+/-)-3-(carbamoylmethyl)-5-methylhexanoic acid; reacting (+/-)-3-(carbamoylmethyl)-5-methylhexanoic acid with (R)-(+)- alpha -phenylethylamine to obtain the (R)-(+)- alpha -phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid; combining the salt with an acid to obtain (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid; and reacting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with a Hofmann reagent to obtain (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
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公开(公告)号：EP0830338B1
公开(公告)日：2001-12-12
申请号：EP96914618.2
申请日：1996-05-13
发明人： GROTE, Todd, Michel , HUCKABEE, Brian, Keith , MULHERN, Thomas , SOBIERAY, Denis, Martin , TITUS, Robert, Daniel
IPC分类号： C07C229/08 , C07C255/19 , C07C255/22 , C07C227/04
CPC分类号： C07C227/34 , C07C227/10 , C07C229/08 , C07C255/19 , C07C255/22
摘要： A method of making (±)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with (II) to form primarily (III); reacting the (III) with a cyanide source to form (IV); decarboxylating the (IV) to form (V); hydrolyzing the (V) with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid, wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, or C3-C6 cycloalkyl. The present invention also provides a method of making (±)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with (II) to form primarily (III); reacting the (III) with a cyanide source to form (IV); decarboxylating the (IV) to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid.
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公开(公告)号：EP0830338A1
公开(公告)日：1998-03-25
申请号：EP96914618.0
申请日：1996-05-13
发明人： GROTE, Todd, Michel , HUCKABEE, Brian, Keith , MULHERN, Thomas , SOBIERAY, Denis, Martin , TITUS, Robert, Daniel
CPC分类号： C07C227/34 , C07C227/10 , C07C229/08 , C07C255/19 , C07C255/22
摘要： A method of making (±)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with (II) to form primarily (III); reacting the (III) with a cyanide source to form (IV); decarboxylating the (IV) to form (V); hydrolyzing the (V) with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid, wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, or C3-C6 cycloalkyl. The present invention also provides a method of making (±)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with (II) to form primarily (III); reacting the (III) with a cyanide source to form (IV); decarboxylating the (IV) to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid.
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