公开(公告)号：EP2421868A1

公开(公告)日：2012-02-29

申请号：EP10766555.6

申请日：2010-04-22

申请人： Brock University

发明人： HUDLICKY, Tomas ,  CARROLL, Robert ,  LEISCH, Hannes ,  MACHARA, Ales ,  WERNER, Lukas ,  ADAMS, David R.

IPC分类号： C07D489/08 ,  C07D489/02 ,  C07D489/12

CPC分类号： C07D489/02 ,  C07D489/04

摘要： The present application describes processes for the synthesis of morphinane and morphinone compounds, useful as pharmaceutical agents. Also included are novel intermediates useful in the preparation of these compounds. The process comprises quaternization of oripavine to provide a mixture of the
R - and
S -isomeric (at the nitrogen) quaternary salts. The
R -isomer is readily isolated and converted to various
N -(
R )-morphinane and
N -(
S )-morphinone compounds. The
R -isomer,
S -isomer or a mixture of
R - and
S -isomers may be demethylated and converted to various morphinane and morphinone compounds.

公开(公告)号：EP2170898A1

公开(公告)日：2010-04-07

申请号：EP08772839.0

申请日：2008-06-30

申请人： Brock University

发明人： CARROLL, Robert ,  LEISCH, Hannes ,  HUDLICKY, Tomas

IPC分类号： C07D489/02 ,  C07B43/04 ,  B01J23/72 ,  B01J23/44

CPC分类号： C07D489/02 ,  C07D451/06

摘要： The present invention relates to a method for N-demethylation of a tertiary N-methylated heterocycle, particularly a morphine or tropane alkaloids or derivatives thereof. The method, comprises reacting said tertiary N-methylated heterocycle with a metal catalyst, for example Pd(OAc)2 or Cu(OAc)2 in the presence of an oxidizing agent such as oxygen or ammonium persulfate.

公开(公告)号：EP2705043B1

公开(公告)日：2016-11-30

申请号：EP12779589.6

申请日：2012-05-02

申请人： Brock University

发明人： HUDLICKY, Tomas ,  WERNER, Lukas ,  WERNEROVA, Martina ,  ENDOMA-ARIAS, Mary Ann ,  MACHARA, Ales

IPC分类号： C07D498/22 ,  C07D489/08

CPC分类号： C07D498/18 ,  C07D489/08 ,  Y02P20/55

公开(公告)号：EP2170898B1

公开(公告)日：2016-05-04

申请号：EP08772839.0

申请日：2008-06-30

申请人： Brock University

发明人： CARROLL, Robert ,  LEISCH, Hannes ,  HUDLICKY, Tomas

IPC分类号： C07D489/02 ,  C07B43/04 ,  B01J23/72 ,  B01J23/44

CPC分类号： C07D489/02 ,  C07D451/06

公开(公告)号：EP2170897A1

公开(公告)日：2010-04-07

申请号：EP08772837.4

申请日：2008-06-30

申请人： Brock University

发明人： CARROLL, Robert James ,  LEISCH, Hannes ,  HUDLICKY, Tomas ,  COX, D. Phillip

IPC分类号： C07D489/02

CPC分类号： C07D489/08 ,  C07D451/06

摘要： The present invention relates to a one-pot method for N-demethylation and/or N-acylation of a tertiary N-methylated heterocycle such as morphine alkaloids or tropane alkaloids The method, exemplified by Scheme 1, comprises reacting said tertiary N-methylated heterocycle with an acylatmg agent in the presence of a Pd metal catalyst.

公开(公告)号：EP2809674A1

公开(公告)日：2014-12-10

申请号：EP13743449.4

申请日：2013-01-30

申请人： Brock University

发明人： HUDLICKY, Tomas ,  ENDOMA-ARIAS, Mary Ann

IPC分类号： C07D489/08

CPC分类号： C07D498/08 ,  C07D489/08 ,  C07D498/20

摘要： The oxazolidine derived from the reaction of oxymorphone with the Burgess reagent, temporariiy protected at 0-3 and C-6, reacts with Grignard or other suitable metallic or organometallic reagents to directly provide, for example, A/-allyl, A/-methylcyclopropyl and /V-methylcyclobutyl derivatives that are further converted into naltrexone, naloxone, nalbuphone and nalbuphine in excellent yields. These morphine analogs can be prepared from the oxazolidine in a one- pot synthesis.

公开(公告)号：EP2705043A1

公开(公告)日：2014-03-12

申请号：EP12779589.6

申请日：2012-05-02

申请人： Brock University

发明人： HUDLICKY, Tomas ,  WERNER, Lukas ,  WERNEROVA, Martina ,  ENDOMA-ARIAS, Mary Ann ,  MACHARA, Ales

IPC分类号： C07D498/22 ,  C07D489/08

CPC分类号： C07D498/18 ,  C07D489/08 ,  Y02P20/55

摘要： A high-yielding method for the N-demethylation of oxycodone- and oxymorphone-N-oxides by the reaction of these compounds with cyclodehydration reagents has been performed. This method has been utilized to improve the synthesis of various morphine analogs, such as naltrexone, nalbuphone and naloxone.

摘要翻译： 已经完成了通过这些化合物与环化脱水剂的反应使羟考酮 - 和羟吗啡酮-N-氧化物N-去甲基化的高产率方法。 该方法已被用于改善各种吗啡类似物如纳曲酮，纳布啡酮和纳洛酮的合成。

公开(公告)号：EP2173754A1

公开(公告)日：2010-04-14

申请号：EP08772838.2

申请日：2008-06-30

申请人： Brock University

发明人： CARROLL, Robert James ,  LEISCH, Hannes ,  HUDLICKY, Tomas ,  COX, D. Phillip

IPC分类号： C07D489/02 ,  C07D489/04

CPC分类号： C07D489/02

摘要： The present invention provides methods for the conversion of the thebaine to a morphine derivative, such as hydrocodone. Novel ketal intermediates fo the conversion are provided. A one-pot procedure for the conversion comprises treating thebaine with an acid in the presence of a metal catalyst.

公开(公告)号：EP2705040B1

公开(公告)日：2016-12-07

申请号：EP12782542.0

申请日：2012-05-04

申请人： Brock University

发明人： HUDLICKY, Tomas ,  MACHARA, Ales

IPC分类号： C07D489/08

CPC分类号： C07D489/02 ,  C07D489/08

公开(公告)号：EP3042908A1

公开(公告)日：2016-07-13

申请号：EP16154522.3

申请日：2012-05-02

申请人： Brock University

发明人： HUDLICKY, Tomas ,  WERNER, Lukas ,  WERNEROVA, Martina ,  ENDOMA-ARIAS, Mary Ann ,  MACHARA, Ales

IPC分类号： C07D498/22 ,  C07D489/08

CPC分类号： C07D498/18 ,  C07D489/08 ,  Y02P20/55

摘要： A compound of Formula V

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent to each other;
R 1 and R 2 are independently selected from C 1-10 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, C 1-10 alkyleneC 6-10 aryl, C 1-10 alkyleneC 3-10 cycloalkyl and PG, except when - - O represents =O, then R 2 is not present;
PG is a protecting group;
R 3 is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 1-10 alkyl, C 2-10 alkenyl, C 6-10 aryl, C 1-10 alkyleneC 6-10 aryl and C 1-10 alkyleneC 3-10 cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R 1 , R 2 and R 3 is/are optionally replaced with F and/or one or more of available atoms in R 1 , R 2 and R 3 is/are optionally replaced with an isotopic label,
or a salt or solvate thereof.

摘要翻译： 式V的化合物，其中----表示单键或双键，条件是两个双键不相邻; R 1和R 2独立地选自C 1-10烷基，C 6-10芳基，C 3-10环烷基，C 1-10亚烷基C 6-10芳基，C 1-10亚烷基C 3-10环烷基和PG，除 当-O - 表示= O时，则R 2不存在; PG是保护基团; R 3选自C 3-10环烷基，C 3-10环烯基，C 1-10烷基，C 2-10烯基，C 6-10芳基，C 1-10亚烷基C 6-10芳基和C 1-10亚烷基C 3-10环烷基; X是抗衡阴离子，R 1，R 2和R 3中的一个或多个可用的氢任选被F替代，和/或任选地被R 1，R 2和R 3中的一个或多个可用原子取代 同位素标记，或其盐或溶剂化物。