公开(公告)号：US07393979B2

公开(公告)日：2008-07-01

申请号：US10560251

申请日：2004-06-08

申请人： Akihiro Ishii ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Masatomi Kanai ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

发明人： Akihiro Ishii ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Masatomi Kanai ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

IPC分类号： C07C209/62 ,  C07C211/05

CPC分类号： C07C209/62 ,  C07B2200/07 ,  C07C209/52 ,  C07C211/15 ,  C07C249/02 ,  C07C251/08

摘要： The present invention relates to a process for producing an optically active 1-alkyl-substituted 2,2,2-trifluoroethylamine, which is an important intermediate of medicines and agricultural chemicals, and which is represented by the formula [3] [in the formula R represents a lower alkyl group of a carbon and * represents an asymmetric carbon], or its salt by subjecting an optically active imine represented by the formula [1] to an asymmetric reduction under hydrogen atmosphere using a metal catalyst of Group VIII to convert it into an optically active secondary amine represented by the formula [2] and then by subjecting the secondary amine or its salt to hydrogenolysis.[Chem. 23]

摘要翻译： 本发明涉及一种制备光学活性的1-烷基取代的2,2,2-三氟乙基胺的方法，它是药物和农药的重要中间体，由式[3] [式 R表示碳的低级烷基，*表示不对称碳]或其盐，通过使用式（1）表示的光学活性亚胺在氢气氛下使用VIII族金属催化剂进行不对称还原，将其转化为 由式[2]表示的光学活性仲胺，然后通过使仲胺或其盐进行氢解。 [Chem。 23]

公开(公告)号：US07388094B2

公开(公告)日：2008-06-17

申请号：US10552463

申请日：2004-04-09

申请人： Akihiro Ishii ,  Takashi Ootsuka ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Koji Ueda

发明人： Akihiro Ishii ,  Takashi Ootsuka ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Koji Ueda

IPC分类号： C07H19/073

CPC分类号： C07H19/067 ,  Y02P20/55

摘要： 1-β-D-Arabinofuranosyluracil in 3′,5′-hydroxyl-protected form is reacted with a trifluoromethanesulfonylating agent in the presence of an organic base to convert it into a 2′-triflate form, and then it is reacted with a fluorinating agent containing “a salt or complex formed by an organic base and hydrofluoric acid” to produce 2′-deoxy-2′-fluorouridine in 3′,5′-hydroxyl-protected form. A deprotecting agent is further caused to act thereon to obtain 2′-deoxy-2′-fluorouridine. The 2′-deoxy-2′-fluorouridine obtained can efficiently be purified by temporarily converting it into a 3′,5′-diacetyl form, recrystallizing the 3′,5′-diacetyl form, and then deacetylating it. Thus, high-purity 2′-deoxy-2′-fluorouridine can be produced.

摘要翻译： 3'，5'-羟基保护形式的1-β-D-阿拉伯呋喃糖尿嘧啶在有机碱的存在下与三氟甲磺酰化剂反应，将其转化为2,3-三氟甲磺酸酯形式，然后与氟化 含有“由有机碱和氢氟酸形成的盐或络合物”的试剂以产生3'，5'-羟基保护形式的2'-脱氧-2'-氟尿苷。 进一步使脱保护剂作用于其上，得到2'-脱氧-2'-氟尿苷。 所得到的2'-脱氧-2'-氟尿苷可以通过暂时转化为3'，5'-二乙酰基形式，重结晶3'，5'-二乙酰基形式，然后脱乙酰化而有效地纯化。 因此，可以制备高纯度2'-脱氧-2'-氟尿苷。

公开(公告)号：US20070191639A1

公开(公告)日：2007-08-16

申请号：US10591669

申请日：2005-02-21

申请人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Katsuhide Suto ,  Koji Ueda

发明人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Katsuhide Suto ,  Koji Ueda

IPC分类号： C07C209/26

CPC分类号： C07C251/24 ,  C07C209/52 ,  C07C209/62 ,  C07C211/29 ,  C07C249/02

摘要： The present invention relates to a method of producing an optically active 1-aryl-2-fluoro-substituted ethylamine compound of the formula [2] or a salt thereof by hydrogenolysis of an optically active secondary amine compound of the formula [1] or a salt thereof in the presence of a transition metal catalyst of Group VIII [Chem. 59] [where Ar represents an aryl group; n represents an integer of 1 or 2; and * represents an asymmetric carbon] [Chem. 60] [where Ar represents an aryl group; n represents an integer of 1 or 2; and * represents an asymmetric carbon].

摘要翻译： 本发明涉及通过氢解式[1]的光学活性仲胺化合物或式[1]的光学活性的1-芳基-2-氟取代的乙胺化合物或其盐， 其盐在第VIII族的过渡金属催化剂存在下[Chem。 59]其中Ar表示芳基; n表示1或2的整数; 和*表示不对称碳] 60] [其中Ar表示芳基; n表示1或2的整数， 和*表示不对称碳]。

公开(公告)号：US07186865B2

公开(公告)日：2007-03-06

申请号：US10476650

申请日：2003-09-05

申请人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

发明人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

IPC分类号： C07C211/00

CPC分类号： C07C209/62 ,  C07B2200/07 ,  C07C211/29 ,  C07C217/58 ,  C07C249/02 ,  C07C251/24

摘要： An optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl derivative represented by the formula 4 is produced by a process including (a) reacting an optically active secondary amine, represented by the formula 1, with an alkylation agent R2—X, in the presence of a base, thereby converting the secondary amine into an optically active tertiary amine represented by the formula 3; and (b) subjecting the tertiary amine to a hydrogenolysis, thereby producing the N-monoalkyl derivative, wherein R represents a fluorine atom, trifluoromethyl group or trifluoromethoxy group, n represents an integer of from 1 to 5, each of R1 and R2 independently represents an alkyl group having a carbon atom number of from 1 to 6, Me represents a methyl group, Ar represents a phenyl group or 1- or 2-naphthyl group, * represents a chiral carbon, and X represents a leaving group.

摘要翻译： 由式4表示的光学活性1-（氟 - ，三氟甲基 - 或三氟甲氧基取代的苯基）烷基胺N-单烷基衍生物通过以下方法制备，该方法包括：（a）使由式1表示的光学活性仲胺与式 烷基化剂R 2 -X在碱的存在下，由此将仲胺转化成由式3表示的光学活性叔胺; 和（b）使叔胺进行氢解，从而制备N-单烷基衍生物，其中R表示氟原子，三氟甲基或三氟甲氧基，n表示1〜5的整数，R 1 独立地表示碳原子数1〜6的烷基，Me表示甲基，Ar表示苯基或1-或2-萘基， *表示手性碳，X表示离去基团。

公开(公告)号：US20060247433A1

公开(公告)日：2006-11-02

申请号：US10552463

申请日：2004-04-09

申请人： Akihiro Ishii ,  Takashi Ootsuka ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Koji Ueda

发明人： Akihiro Ishii ,  Takashi Ootsuka ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Koji Ueda

IPC分类号： C07H19/12

CPC分类号： C07H19/067 ,  Y02P20/55

摘要： 1-β-D-Arabinofuranosyluracil in 3′,5′-hydroxyl-protected form is reacted with a trifluoromethanesulfonylating agent in the presence of an organic base to convert it into a 2′-triflate form, and then it is reacted with a fluorinating agent containing “a salt or complex formed by an organic base and hydrofluoric acid” to produce 2′-deoxy-2′-fluorouridine in 3′,5′-hydroxyl-protected form. A deprotecting agent is further caused to act thereon to obtain 2′-deoxy-2′-fluorouridine. The 2′-deoxy-2′-fluorouridine obtained can efficiently be purified by temporarily converting it into a 3′,5′-diacetyl form, recrystallizing the 3′,5′-diacetyl form, and then deacetylating it. Thus, high-purity 2′-deoxy-2′-fluorouridine can be produced.

摘要翻译： 3'，5'-羟基保护形式的1-β-D-阿拉伯呋喃糖尿嘧啶在有机碱的存在下与三氟甲磺酰化剂反应，将其转化为2,3-三氟甲磺酸酯形式，然后与氟化 含有“由有机碱和氢氟酸形成的盐或络合物”的试剂以产生3'，5'-羟基保护形式的2'-脱氧-2'-氟尿苷。 进一步使脱保护剂作用于其上，得到2'-脱氧-2'-氟尿苷。 所得到的2'-脱氧-2'-氟尿苷可以通过暂时转化为3'，5'-二乙酰基形式，重结晶3'，5'-二乙酰基形式，然后脱乙酰化而有效地纯化。 因此，可以制备高纯度2'-脱氧-2'-氟尿苷。

公开(公告)号：US20060128976A1

公开(公告)日：2006-06-15

申请号：US11347390

申请日：2006-02-06

申请人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

发明人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

IPC分类号： C07D317/00 ,  C07D309/00

CPC分类号： C07D317/22 ,  C07C43/315 ,  C07C45/57 ,  C07C45/59 ,  C07C45/60 ,  C07C49/84 ,  C07D317/16 ,  C07C49/80

摘要： A process for producing a brominated acetal (represented by the formula 3) includes (a) brominating a trifluoromethyl-substituted acetophenone by Br2 in the presence of an alkylene diol. It is optional to produce a trifluoromethyl-substituted 2-alkoxyacetophenone derivative (represented by the formula 9) by (b) reacting the brominated acetal with a metal alkoxide, thereby converting the brominated acetal into an ether; and (c) hydrolyzing the ether in the presence of an acid catalyst to remove an acetal group from the ether, thereby producing the 2-alkoxyacetophenone derivative. Alternatively, the 2-alkoxyacetophenone can be produced by (a) reacting a trifluoromethyl-substituted phenacyl halide with an acetalization agent, thereby converting the phenacyl halide into an acetal; (b) reacting the acetal with a metal alkoxide, thereby converting the acetal into an ether; and (c) hydrolyzing the ether in the presence of an acid catalyst to remove the acetal group from the ether.

摘要翻译： 制备溴化缩醛的方法（由式3表示）包括（a）在亚烷基二醇的存在下用Br 2 H 3溴化三氟甲基取代的苯乙酮。 （b）使溴化缩醛与金属醇盐反应，从而将溴化缩醛转化成醚，任选地制备三氟甲基取代的2-烷氧基苯乙酮衍生物（由式9表示） 和（c）在酸催化剂的存在下水解醚，以从乙醚中除去缩醛基，从而制备2-烷氧基苯乙酮衍生物。 或者，2-烷氧基苯乙酮可以通过以下方法制备：（a）使三氟甲基取代的苯甲酰甲基卤化物与缩醛化剂反应，从而将苯甲酰甲酰卤转化成缩醛; （b）使缩醛与金属醇盐反应，从而将缩醛转化成醚; 和（c）在酸催化剂存在下水解该醚，以从乙醚中除去缩醛基。

公开(公告)号：US07053248B2

公开(公告)日：2006-05-30

申请号：US10473399

申请日：2003-08-08

申请人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

发明人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

IPC分类号： C07C45/61

CPC分类号： C07D317/22 ,  C07C43/315 ,  C07C45/57 ,  C07C45/59 ,  C07C45/60 ,  C07C49/84 ,  C07D317/16 ,  C07C49/80

摘要： A process for producing a brominated acetal (represented by the formula 3) includes (a) brominating a trifluoromethyl-substituted acetophenone by Br2 in the presence of an alkylene diol. It is optional to produce a trifluoromethyl-substituted 2-alkoxyacetophenone derivative (represented by the formula 9) by (b) reacting the brominated acetal with a metal alkoxide, thereby converting the brominated acetal into an ether; and (c) hydrolyzing the ether in the presence of an acid catalyst to remove an acetal group from the ether, thereby producing the 2-alkoxyacetophenone derivative. Alternatively, the 2-alkoxyacetophenone can be produced by (a) reacting a trifluoromethyl-substituted phenacyl halide with an acetalization agent, thereby converting the phenacyl halide into an acetal; (b) reacting the acetal with a metal alkoxide, thereby converting the acetal into an ether; and (c) hydrolyzing the ether in the presence of an acid catalyst to remove the acetal group from the ether.

摘要翻译： 制备溴化缩醛的方法（由式3表示）包括（a）在亚烷基二醇的存在下用Br 2 H 3溴化三氟甲基取代的苯乙酮。 （b）使溴化缩醛与金属醇盐反应，从而将溴化缩醛转化成醚，任选地制备三氟甲基取代的2-烷氧基苯乙酮衍生物（由式9表示） 和（c）在酸催化剂的存在下水解醚，以从乙醚中除去缩醛基，从而制备2-烷氧基苯乙酮衍生物。 或者，2-烷氧基苯乙酮可以通过以下方法制备：（a）使三氟甲基取代的苯甲酰甲基卤化物与缩醛化剂反应，从而将苯甲酰甲酰卤转化成缩醛; （b）使缩醛与金属醇盐反应，从而将缩醛转化成醚; 和（c）在酸催化剂存在下水解该醚，以从乙醚中除去缩醛基。

公开(公告)号：US07459586B2

公开(公告)日：2008-12-02

申请号：US10591669

申请日：2005-02-21

申请人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Katsuhide Suto ,  Koji Ueda

发明人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Katsuhide Suto ,  Koji Ueda

IPC分类号： C07C209/62 ,  C07C211/00 ,  C07C251/00

CPC分类号： C07C251/24 ,  C07C209/52 ,  C07C209/62 ,  C07C211/29 ,  C07C249/02

摘要： The present invention relates to a method of producing an optically active 1-aryl-2-fluoro-substituted ethylamine compound of the formula [2] or a salt thereof by hydrogenolysis of an optically active secondary amine compound of the formula [1] or a salt thereof in the presence of a transition metal catalyst of Group VIII[Chem. 59] [where Ar represents an aryl group; n represents an integer of 1 or 2; and * represents an asymmetric carbon] [Chem. 60] [where Ar represents an aryl group; n represents an integer of 1 or 2; and * represents an asymmetric carbon].

摘要翻译： 本发明涉及通过氢解式[1]的光学活性仲胺化合物或式[1]的光学活性的1-芳基-2-氟取代的乙胺化合物或其盐， 其盐在第VIII族的过渡金属催化剂存在下[Chem。 59]其中Ar表示芳基; n表示1或2的整数; 和*表示不对称碳] 60] [其中Ar表示芳基; n表示1或2的整数; 和*表示不对称碳]。

公开(公告)号：US07368609B2

公开(公告)日：2008-05-06

申请号：US11705089

申请日：2007-02-12

申请人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

发明人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

IPC分类号： C07C211/00

CPC分类号： C07C209/62 ,  C07B2200/07 ,  C07C211/29 ,  C07C217/58 ,  C07C249/02 ,  C07C251/24

摘要： An optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl derivative represented by the formula 4 is produced by a process including (a) reacting an optically active secondary amine, represented by the formula 1, with an alkylation agent R2—X, in the presence of a base, thereby converting the secondary amine into an optically active tertiary amine represented by the formula 3; and (b) subjecting the tertiary amine to a hydrogenolysis, thereby producing the N-monoalkyl derivative, wherein R represents a fluorine atom, trifluoromethyl group or trifluoromethoxy group, n represents an integer of from 1 to 5, each of R1 and R2 independently represents an alkyl group having a carbon atom number of from 1 to 6, Me represents a methyl group, Ar represents a phenyl group or 1- or 2-naphthyl group, * represents a chiral carbon, and X represents a leaving group.

摘要翻译： 由式4表示的光学活性1-（氟 - ，三氟甲基 - 或三氟甲氧基取代的苯基）烷基胺N-单烷基衍生物通过以下方法制备，该方法包括：（a）使由式1表示的光学活性仲胺与式 烷基化剂R 2 -X在碱的存在下，由此将仲胺转化成由式3表示的光学活性叔胺; 和（b）使叔胺进行氢解，从而制备N-单烷基衍生物，其中R表示氟原子，三氟甲基或三氟甲氧基，n表示1〜5的整数，R 1 独立地表示碳原子数1〜6的烷基，Me表示甲基，Ar表示苯基或1-或2-萘基， *表示手性碳，X表示离去基团。

公开(公告)号：US07189863B2

公开(公告)日：2007-03-13

申请号：US11347390

申请日：2006-02-06

申请人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

发明人： Akihiro Ishii ,  Masatomi Kanai ,  Yokusu Kuriyama ,  Manabu Yasumoto ,  Kenjin Inomiya ,  Takashi Ootsuka ,  Koji Ueda

IPC分类号： C07D319/06

CPC分类号： C07D317/22 ,  C07C43/315 ,  C07C45/57 ,  C07C45/59 ,  C07C45/60 ,  C07C49/84 ,  C07D317/16 ,  C07C49/80

摘要： A process for producing a brominated acetal (represented by the formula 3) includes (a) brominating a trifluoromethyl-substituted acetophenone by Br2 in the presence of an alkylene diol. It is optional to produce a trifluoromethyl-substituted 2-alkoxyacetophenone derivative (represented by the formula 9) by (b) reacting the brominated acetal with a metal alkoxide, thereby converting the brominated acetal into an ether; and (c) hydrolyzing the ether in the presence of an acid catalyst to remove an acetal group from the ether, thereby producing the 2-alkoxyacetophenone derivative. Alternatively, the 2-alkoxyacetophenone can be produced by (a) reacting a trifluoromethyl-substituted phenacyl halide with an acetalization agent, thereby converting the phenacyl halide into an acetal; (b) reacting the acetal with a metal alkoxide, thereby converting the acetal into an ether; and (c) hydrolyzing the ether in the presence of an acid catalyst to remove the acetal group from the ether

摘要翻译： 制备溴化缩醛的方法（由式3表示）包括（a）在亚烷基二醇的存在下用Br 2 H 3溴化三氟甲基取代的苯乙酮。 （b）使溴化缩醛与金属醇盐反应，从而将溴化缩醛转化成醚，任选地制备三氟甲基取代的2-烷氧基苯乙酮衍生物（由式9表示） 和（c）在酸催化剂的存在下水解醚，以从乙醚中除去缩醛基，从而制备2-烷氧基苯乙酮衍生物。 或者，2-烷氧基苯乙酮可以通过以下方法制备：（a）使三氟甲基取代的苯甲酰甲基卤化物与缩醛化剂反应，从而将苯甲酰甲酰卤转化成缩醛; （b）使缩醛与金属醇盐反应，从而将缩醛转化成醚; 和（c）在酸催化剂存在下水解该醚，以从乙醚中除去缩醛基