Methods for one-pot N-demethylation/N-functionalization of morphine and tropane alkaloids

31 Pages·2015·2.64 MB·English

USOO8962841B2
(12) Unlted States Patent (10) Patent N0.2 US 8,962,841 B2
Hudlicky et a]. (45) Date of Patent: *Feb. 24, 2015
(54) METHODS FOR ONE-POT 6,388,079 B1 5/2002 Wu et al.
N-DEMETHYLATION/N-FUNCTIONAL g} gevwo 9t al~
IZATION 0F MORPHINE AND TROPANE 6,790,959 B1 * 9/2004 Lirrllugt3 al 546/44
ALKALOIDS 6,864,370 B1 * 3/2005 Lin et al. ....................... .. 546/44
7,935,820 B2 5/2011 Carroll et al.
(75) Inventors: Tomas Hudlicky, St. Catharines (CA); 7,999,104 B2 * 8/2011 Carroll et a1. . . . . . . . . . . .. 546/45
Robert James Carroll, Hens (GB); 8,318,937 B2 * 11/2012 Mitchell et al. . . . . . . . .. 546/45
Hannes Leisch’ Umerach am Attersee 8,431,701 B2 : 4/2013 HUdSOIl et ill ~ ~ ~ ~ ~ ~ ~ ~ ~~ 546/44
(AT); Ales Machara’ Brevnov (CZ); 8,436,174 B2 5/2013 Cantrell et al. ............... .. 546/45
Lukas WernFr’ Kadan (CZ); Mary Ann FOREIGN PATENT DOCUMENTS
Endoma-Arlas, Quezon (PH)
CA 1244825 11/1988
(73) Assignee: Brock University, St. Catharines, WO 98/05667 2/ 1998
Ontario (CA) W0 01/34608 5/2001
W0 WO 2004/108090 A2 * 12/2004
*
( * ) Notice: pSautbejnetc ti st o eaxntye nddiesdcl aoirm eard,j utshtee tde urnmd oefr t h3i5s WO W022200%0055%/21§1g3g5(517) A2 12/2005
U.S.C. 154(b) by 402 days. wo 2006/104656 10/2006
_ _ _ _ _ WO 2011/032214 A1 3/2011
Thls patent 1s 511131601 to a termlnal d1s
claimer. OTHER PUBLICATIONS
(21) Appl_ No; 13/178,623 Johnstone, RA. et al. Heterogeneous Catalytic Transfer Hydrogena
tion and Its Relation to Other Methods for Reduction of Organic
(22) Filed: Jul. 8, 2011 Compounds. Chem. Rev. 1985, vol. 85, p. 141, C1.*
Birch, AJ. et al. Lateral Control of Skeletal Rearrangement by
(65) Prior Publication Data Complexation of Thebaine with Fe(CO)3. Tetrahedron Letters. 1985,
vol. 26, p. 502, lines 1-7.*
Us 2011/0313163 A1 Dec- 22, 2011 Birch, AJ. et al. Lateral Control of Skeletal Rearrangement by
Complexation of Thebaine with Fe(CO)3. Tetrahedron Letters. 1985,
. . vol. 26, p. 502.*
Related U's' Apphcatlon Data Johnstone, RA. et al. Heterogeneous Catalytic Transfer Hydrogena
(63) Continuation-impart of application No, 11/771,191, tion and Its Relation to Other Methods for Reduction of Organic
?led on Jun. 29, 2007, now Pat. No. 7,999,104. Compounds~ Chem ReV~ 1935, V01 85,11 141~*
Dorwold, FZ. Side Reactions in Organic Synthesis. Wiley. 2005,
(51) Int'Cl' gefasce'i RA t l C tl ' El ' 2000 290*
an an en, . e a . a a ys1s. seV1er. , p. .
0 Sugi, Yoshihiro; Hanaoka, Taka-Aki; Takeuchi, Kazuhiko;
( ' ) Matsuzaki, Hiroki Watanabe; Bando, Ken-Ichiro, “Dealkylation of
C0 7D 49 1/0 0 (200601) N,N-dialkylanilines over transition metal catalysts in the presence of
C0 7D 49 8/0 0 (200601) ammonia, water and hydrogen”, Applied Catalysis A.: General, 103
C07D 513/00 (2006.01) (1993), 43-53.
C07D 515/00 (2006.01) Goo,Yukon; Shi, Hongmei; Huo, Shuying; Shen, Shigang, “Kinetics
C07D 489/00 (200601) and mechanism of oxidation of N-methylethylamine by
(‘07D 489/08 (200601) bis(hydrogenperiodato)argentate(III) complex anion”, Transition
Met Chem (2011), 36159-64.
C07D 221/22 (2006 01) Suzuki, M., et al. “Synthesis and evaluation of novel 2-oxo-1,2
C 0 7D 489/02 2006'01 dihydro-3 -quinolinecarboxamide derivatives as potent and selective
( ' ) serotonin 5-HT4 receptor agonists.” Chem Pharm Bull (Tokyo). Jan.
C07D 489/12 (2006.01) 2001;49(1),29_39‘
(52) US. Cl. (Continued)
CPC .......... .. C07D 451/06 (2013.01); C07D 221/22
(2013.01); C07D 489/02 (2013.01); C07D _ _ _ _
489/08 (2013.01); C07D 489/12 (2013.01) Primary Exam/"er * R1121 Desa}
USPC .............................. .. 546/45; 546/46; 514/282 ASS/'SmmEW/"iner * Ben S Mlchelson
(58) Field of Classi?cation Search (74) Arm/My. A8911. or Firm *Dann, Dorfman, Herrell
CPC .. C07D 471/00; C07D 491/00; C07D 498/00; and Sklllman; Pamck 1- Hagan
CO7D 513/00; CO7D 515/00; CO7D 489/00;
C07D 489/08 (57) ABSTRACT
See application ?le for complete search history. The present invention provides a method for the N-demethy
lation and N-functionalization of an N-methylated hetero
(56) References Clted cycle such as a morphine alkaloid or tropane alkaloid. The
method comprises reacting the heterocycle with an function
US. PATENT DOCUMENTS
alization agent in the presence of a transition metal catalyst in
4,472,253 A 9/1984 Schwartz air or in the presence of an oxidant.
4,613,668 A 9/1986 Rice
6,376,221 B1* 4/2002 Fist et a1. .................... .. 435/118 36 Claims, 1 Drawing Sheet
US 8,962,841 B2
Page 2
(56) References Cited Gersterg, S., et al. “Bis-dealkylation of Quaternary Ammonium
Salts.” Tetrahedron Letters. 1973;15:1269-1272.
Iijima, I., et al. “Studies in the (+) Morphinan series I. An alternate
OTHER PUBLICATIONS conversion of (+) -dihydrocodeinone into (+)-codeine.” Heterocycles,
Lee, S., et al. “Preparation of N-alkylnorpavines via competitive 1997;611157-1165.
N-dealkylation of quaternary pavines.” Heterocycles. Ripper, J .A., et al. “Photochemical N-demethylation of alkaloids.”
l996;43(7):l403-l4l4. Bioorg Med Chem Lett. Feb. 26, 2001;l l(4):443-5.
Senokuchi, K., et al. “Synthesis and biological evaluation of (+)
epibatidine and the congeners.” Synlett. May 1994; 343-344. * cited by examiner
US. Patent Feb. 24, 2015 US 8,962,841 B2
US 8,962,841 B2
1 2
METHODS FOR ONE-POT -continued
N-DEMETHYLATION/N-FUNCTIONALIZATION
OF MORPHINE AND TROPANE ALKALOIDS
CROSS-REFERENCE TO RELATED
APPLICATIONS
The present application is a continuation-in-part of co
pending US. patent application Ser. No. 11/771,191 ?led on
Jun. 29, 2007, the contents of which are incorporated herein
by reference in their entirety. naltrexone, R I ]
FIELD OF THE INVENTION
naloxone, R I ally>l 59
The present invention relates to methods for N-demethy
nalbuphone, R I
lation and N-functionalization of various N-heterocyclic
compounds, in particular morphine and tropane alkaloids.
BACKGROUND OF THE INVENTION 20
The semisynthesis of morphine-derived antagonists, such
as naloxone, nalbuphone, naltrexone and buprenorphine (see
Scheme 1), and other medicinally signi?cant compounds,
from opium-derived natural products traditionally involves 25
standard procedures for demethylation followed by subse
quent procedures such as oxidation for the introduction of a
C-14 hydroxyl group.
30
Natural opiate alkoloids Semisynthetic pharmaceuticals
buprenorphine
The challenge rests in the formal exchange of the N-methyl
group of natural opiates for other functional groups, such as
the N-cyclopropylmethyl, N-allyl, or N-cyclobutylmethyl
functionality found in naltrexone, naloxone, nalbuphone and
buprenorphine. The N-demethylation protocols previously
40 reported include the von Braun reaction employing cyanogen
bromide (Von Braun, J Chem. Ber. 1980, 33, 1438), chloro
morphine, R I H formate reagents (Cooley, J. H.; Evain, E. J. Synthesis 1989,
codeine, R I Me 1; Olofson, R. A. et al. J Org. Chem. 1984, 49, 2081), pho
tochemical methods (Ripper, J. A., et al. Biorg. &Med. Chem.
45 Len. 2001, 11, 443-445), demethylation of N-oxides
[Polonovski reaction: (a) Kok, G. et al. Adv. Synlh. Calal.
2009, 351, 283; (b) Dong, Z. et al. J. Org. Chem. 2007, 72,
9881; (c) Smith, C. et al. PCT Patent Application Publication
No. WO 2005/ 028483], as well as microbial [(a) Madyashtha,
50 K. M. et al. Proc. Indian Acad. Sci. 1984, 106, 1203; (b)
Madyastha, K. M. et al. J. Chem. Soc. Perkin Trans. 1, 1994,
911] and enzymatic (Chaudhary, V. et al. Collect. Czech.
Chem Cnmrmm 7009 74 1 179) methods The disadvan
thebaine, R I Me tages of these methods are that the reagents are highly toxic
oripavine, R I H
55 (cyanogen bromide and ethylchloroformate) or proceed in
poor yields (Polonovski and enzymatic methods) requiring
signi?cant puri?cation of the desired secondary amine. The
secondary amines are then converted to the corresponding
products by alkylation.
60 Therefore any method that avoids these standard proce
dures may hold immense commercial potential for the pro
duction of morphine-derived alkaloids, such as naloxone,
naltrexone, nalbuphone, buprenorphine and other medici
nally signi?cant compounds.
oxycodone, R I Me 65 Current methods for N-demethylation of morphine alka
oxymorphone, R I H loids are time consuming, expensive and hazardous. Thus
there was an unmet need for improvement in such methods.
US 8,962,841 B2
3 4
Furthermore, there is an increasing demand that production
methods be environmentally friendly.
SUMMARY OF THE INVENTION R3 is selected from H, OH, OCl_lOalkyl, OC(O)Cl_lOalkyl,
OC(O)OC1_10alkyl and OPG2 or R3 is not present when the
The present invention provides a one-pot method for carbon atom to which it is attached is sp2 hybridized, or R3
N-demethylation and functionalization of N-methylated and R5’ form a CH24CH2 linker between the carbon atoms
compounds, particularly morphine alkaloids and their deriva to which they are attached;
R4 is selected from H, C 1_ loalkyl, C(O)Cl_loalkyl, hydroxyl
tives or tropane alkaloids and their derivatives. Thus, the
substituted C l_10alkyl, and PG3 -O-substituted C l_10alkyl;
present invention elucidates conditions for a one-pot oxida
tive N-demethylation and N-functionalization of morphine is selected from OH, OC l_10alkyl, OC(O)C 1_ loalkyl,
OC(O)OC1_10alkyl and OPG4 when the -_-; to which it is
and tropane alkaloids that is performed at lower temperatures
attached is a single bond, or R5 is O when the 2 to which
than prior art methods, is cost effective and safe.
it is attached is a double bond,
The present invention therefore includes a method for the
R5’ is either not present or R5 v and R3 form a CHZiCH2 linker
N-demethylation and functionalization of N-methylated het
between the carbon atoms to which they are attached, only
erocycles comprising reacting an N-methylated heterocycle
when R5 = is Rsi and the carbon to which it is attached
with a functionalization agent in the presence of a transition is sp3 hybridized;
metal catalyst. In a further embodiment, the method further R6 and R6’ are independently selected from C3_10cycloalkyl,
comprises reacting the N-methylated heterocycle with the C3_10heterocycloalkyl, C3_locycloalkenyl, Cl_20alkyl,
20
functionalization agent in the presence of a transition metal C2_20alkenyl, C2_20alkynyl, C6_10aryl and C5_10heteroaryl,
catalyst and an oxidant. each of the latter eight groups being unsubstituted or sub
In one embodiment of the invention, the N-methylated stituted with one or more substituents independently
compound is a morphine alkaloid. Accordingly, the present selected from R7, ORS, SiR7R7'R8, NR8R8', SR8, S(O)R7,
application includes a method of preparing a compound of 25 SOzR7, halo, CN and NOZ;
Formula I: R7 and R7’ are independently selected from C l_6alkyl,
C6_10aryl and C1_6alkyleneC6_lOaryl;
R8 and R8’ are independently selected from H, PGS, C l_6alkyl,
(I) C6_10aryl and C1_6alkyleneC6_lOaryl;
30 1-; represents a single or double bond, provided that two
double bonds are not adjacent to each other;
PGl, PGZ, PG3 , PG4 and PG5 are independently, a protecting
group that is removable after the preparation of the com
pound of Formula I; and
35 LG is a leaving group,
wherein, when (a) R1, R8 and/or R8’ are H; (b) R3 and/ or R5 is
OH; and/or (c) R4 is hydroxyl-substituted Cl_10alkyl, the
method further comprises removal of any R2 group in R1,
R8, R8, R3, R5 and/or R4.
40 In an embodiment of the invention, the method of prepar
ing the compound of Formula I further comprises reacting the
compound of Formula II with a compound of Formula III or
IV, in the presence of a transition metal catalyst and an oxi
dant.
(H)
45 In an embodiment, the compounds of Formula II are
selected from thebaine, oripavine, l4-hydroxycodeinone,
l4-hydroxymorphinone, morphine, codeine, hydromor
phone, hydrocodone, oxymorphone, oxycodone, hydromor
phol, oxymorphol and [5a,70t]-(l ,l-dimethylethyl)-4,5-ep
50 oxy- l 8, l 9-dihydro-3 ,6-dimethoxy-0t, l7-dimethyl-6, l 4
ethenomorphinan-7-methanol. In a particular embodiment of
this aspect the present invention there is provided a one-pot
method for N-demethvlation and subsequent functionalim
tion of hydrocodone. In another particular aspect of the
55 present invention, there is provided a one-pot method for the
N-demethylation and subsequent functionalization of [5a,
7a]-(l,l-dimethylethyl)-4,5-epoxy-l8,19-dihydro-3,6
in the presence of a transition metal catalyst and a compound
dimethoxy-(x, l 7-dimethyl-6, l4-ethenomorphinan-7-metha
of Formula III or IV:
nol, for example for the preparation of buprenorphine. In
RZ-LG (III) 60 another particular aspect of the present invention, there is
provided a one-pot method for the N-demethylation and sub
sequent functionalization of oxymorphone, for example for
the preparation of naltrexone, nalbuphone or naloxone.
under conditions to provide the compound of Formula I, In another embodiment of the invention, the N-methylated
wherein, 65 compound is a tropane alkaloid. Accordingly, the present
R1 is selected from H, Cl_10alkyl, C(O)C 1_ loalkyl, C(O)OC1_ invention includes a method of preparing a NiRZ-function
ioalkyl and PGl; alized tropane alkaloid comprising reacting an N-methyl tro
US 8,962,841 B2
5 6
pane alkaloid in the presence of a transition metal catalyst and lyst Wherein the active metal is selected from W, V, Cu, Fe,
a compound of Formula III or IV: Ru, Co, Rh, Ir, Ni, Pd, Pt, Ge, Sn, Os, Cu, Ag,Au and Pb, and
mixtures thereof.
RZ-LG (III) In one embodiment, the method comprises the steps of
treating the N-methylated compound With palladium, at least
one anhydride but Without any added solvent. In another
R6:C:O (IV)
embodiment the palladium source is one of Pd(OAc)2 or
Wherein,
PdCl2 and the anhydride is acetic anhydride. In another
embodiment the palladium source is Pd(OAc)2.
In another embodiment, the method comprises the step of
treating the N-methylated compound With a catalyst, at least
R6 and R6’ are independently selected from C3_locycloalkyl,
C3_10heterocycloalkyl, C3_locycloalkenyl, Cl_20alkyl, one solvent and at least one dicarbonate.
C2_2Oalkenyl, C2_20alkynyl, C6_10aryl and C5_10heteroaryl, The present invention also includes a method for the prepa
ration of naltrexone or nalbuphone from a compound of For
each of the latter eight groups being unsubstituted or sub
mula I(a):
stituted With one or more substituents independently
selected from R7, ORS, SiR7R7'R8, NRSRsv, SR8, S(O)R7,
SOzR7, halo, CN and NO2;
R7 and R7’ are independently selected from C l_6alkyl, 1(a)
C6_10aryl and C1_6alkyleneC6_lOaryl;
20
R8 and R8’ are independently selected from H, PG5 , C l_6alkyl,
C6_10aryl and C1_6alkyleneC6_lOaryl;
PG5 is a protecting group that is removable after the prepara
tion of the NiRz-functionalized tropane alkaloid; and
LG is a leaving group, 25
Wherein, When R8 and/or R8’ are H; the method further com
prises removal of any R2 group in R8 and/or Rsv. R5
In an embodiment of the invention, the method of prepar
ing a NiRz-functionalized tropane alkaloid further com
prises reacting a N-methyl tropane alkaloid With a compound 30 wherein R1 is H, R3 is OH, 2 is a double bond, R5 is O and
R2 is C(O)cyclopropyl or C(O)cyclobutyl, prepared using the
of Formula III or IV, in the presence of a transition metal
method of the invention, comprising:
catalyst and an oxidant.
In an embodiment of the invention, the N-methyl tropane (a) treating the compound of Formula I(a) With a reducing
alkaloid is selected from tropinone, tropane, tropine, atro agent under conditions to provide naltrexone or nalbu
pine, cocaine or any other bicyclo-[3 .2.l]-azabicyclic methy 35 phone.
lamine. The present invention also includes a method for the prepa
In one embodiment of the invention, the compound of ration of naltrexone, nalbuphone or naloxone from a com
Formula III is an acylating agent. In another embodiment, the pound of Formula I(a):
acylating agent is an anhydride. Suitable anhydrides include,
but are not limited to acetic anhydride, iso-butyric anhydride, 40
n-propanoic anhydride, decanoic anhydride, dodecanoic I(a)
anhydride, cyclopropylcarbonyl anhydride, cyclobutylcarbo
nyl anhydride, allylcarbonyl anhydride and anhydrides
derived from C1_ 19 carboxylic acids and mixed anhydrides
derived therefrom. 45
In another embodiment of the invention, the acylating
agent is a dicarbonate. Suitable dicarbonates include carbon
ates derived from C1_19 alcohols, dimethyl dicarbonate, di
tert-amyl dicarbonate, di-tent-butyl dicarbonate, diallyl pyro
carbonate, dibenzyl dicarbonate, diethyl pyrocarbonate,
50
dimethyl dicarbonate, erythritol bis(carbonate) and mixed
carbonates derived thereof. wherein R1 is H, R3 is OH, I; is a double bond, R5 is O, R2
In yet another aspect of the present invention there is pro is C(O)R6, R6 is selected from C3_10cycloalkyl, C3_10het
vided a one-pot method for N-demethylation and subsequent erocycloalkyl, C3_10cycloalkenyl, Cl_20alkyl, C2_2Oalk
carboxylation of morphine or tropane alkaloids and their 55 enyl, C2_20alkynyl, C6_10aryl and C5_10heteroaryl, each of
derivatives to the corresponding carbamates. In this embodi the latter eight groups being unsubstituted or substituted
ment, the compound of Formula III is suitably a dicarbamic With one or more substituents independently selected from
anhydride such as N,N'-dimethylcarbamic anhydride, N,N' R7, ORS, SiR7R7'R8, NR8R8', SR8, S(O)R7, SOzR7, halo,
diethylcarbamic anhydride, diphenylcarbamic acid anhy CN and NO2;
dride, N,N'-diphenylcarbonic acid anhydride, N,N'-diphenyl 60 R7 and R7’ are independently selected from Cl_6alkyl,
dicarbonic diamide, N,N'-(oxydicarbonyl)bisglycine C6_10aryl and Cl_6alkyleneC6_lOaryl; and
dimethylester, pyrrole-l-carboxylic anhydride or a mixture R8 and R8’ are independently selected from H, Cl_6alkyl,
thereof. C6_10aryl and Cl_6alkyleneC6_10aryl, prepared using the
In an embodiment of the invention, the catalyst is a transi method of the invention, the method comprising
tion metal catalyst selected from the group consisting of 65 (a) treating the compound of Formula I(a) under deacylating
Pd(OAc)2, PdClz, PdC12(PPh3)4, PdBrZ, Pd(acac)2, conditions followed by an alkylating reagent of the formula
Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, or is a transition metal cata cyclopropyl-CH2-LG, cyclobutyl-CHZ-LG or
US 8,962,841 B2
7 8
CH2:CHiCH2-LG, wherein LG is a leaving group, The term “suitable” as used herein means that the selection
under conditions to provide naltrexone, nalbuphone or of the particular compound or conditions would depend on
naloxone, respectively. the speci?c synthetic manipulation to be performed, and the
The present invention also includes a method for the pre identity of the molecule(s) to be transformed, but the selec
paring of buprenorphine from a compound of the Formula tion would be well within the skill of a person trained in the
l(e): art. All process/method steps described herein are to be con
ducted under conditions suf?cient to provide the product
shown. A person skilled in the art would understand that all
reaction conditions, including, for example, reaction solvent,
1(6)
reaction time, reaction temperature, reaction pressure, reac
tant ratio and whether or not the reaction should be performed
under an anhydrous or inert atmosphere, can be varied to
optimize the yield of the desired product and it is within their
skill to do so.
In embodiments of the application, the compounds
described herein have at least one asymmetric centre. Where
compounds possess more than one asymmetric centre, they
may exist as diastereomers. It is to be understood that all such
isomers and mixtures thereof in any proportion are encom
20 passed within the scope of the present application. It is to be
further understood that while the stereochemistry of the com
wherein R1 is H, R4 is C(O)Me or C(Me)(OH)(t-butyl), R5 is pounds may be as shown in any given compound listed herein,
OMe and R2 is C(O)cyclopropyl, prepared using the such compounds may also contain certain amounts (e.g. less
method the invention, comprising either: than 50%, suitably less than 20%, suitably less than 10%,
(a) treating the compound of Formula l(e) with a reducing 25 more suitably less than 5%) of compounds having alternate
agent under conditions to provide buprenorphine; or stereochemistry.
(b) treating the compound of Formula l(e) under deacylating In understanding the scope of the present disclosure, the
conditions followed by an alkylating reagent of the formula term “comprising” and its derivatives, as used herein, are
cyclopropyl-CHZ-LG, wherein LG is a leaving group, intended to be open ended terms that specify the presence of
under conditions to provide buprenorphine. 30 the stated features, elements, components, groups, integers,
Other features and advantages of the present invention will and/ or steps, but do not exclude the presence of other unstated
become apparent from the following detailed description. It features, elements, components, groups, integers and/or
should be understood, however, that the detailed description steps. The foregoing also applies to words having similar
and the speci?c examples while indicating embodiments of meanings such as the terms, “including”, “having” and their
the invention are given by way of illustration only, since 35 derivatives. The term “consisting” and its derivatives, as used
various changes and modi?cations within the spirit and scope herein, are intended to be closed terms that specify the pres
of the invention will become apparent to those skilled in the ence of the stated features, elements, components, groups,
art from this detailed description. integers, and/ or steps, but exclude the presence of other
unstated features, elements, components, groups, integers
BRIEF DESCRIPTION OF THE DRAWINGS 40 and/or steps. The term “consisting essentially of”, as used
herein, is intended to specify the presence of the stated fea
These and other features of the invention will become more tures, elements, components, groups, integers, and/ or steps as
apparent from the following description in which reference is well as those that do not materially affect the basic and novel
made to the appended drawings wherein: characteristic(s) of features, elements, components, groups,
FIG. 1 shows an X-ray structure for N-acetylhydrocodone. 45 integers, and/or steps.
Terms of degree such as “substantially”, “about” and
DETAILED DESCRIPTION “approximately” as used herein mean a reasonable amount of
deviation of the modi?ed term such that the end result is not
I. De?nitions signi?cantly changed. These terms of degree should be con
50 strued as including a deviation of at least 15% of the modi?ed
Unless otherwise indicated, the de?nitions and embodi term if this deviation would not negate the meaning of the
ments described in this and other sections are intended to be word it modi?es.
applicable to all embodiments and aspects of the application The term “alkyl” as used herein, whether it is used alone or
herein described for which they are suitable as would be as part of another group, means straight or branched chain,
understood by a person skilled in the art. 55 saturated alkyl groups. The term Cl_6alkyl means an alkyl
As used in this application, the singular forms “a”, “an” and group having 1, 2, 3, 4, 5, or 6 carbon atoms. The term
“the” include plural references unless the content clearly C1_2Oalkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9,
dictates otherwise. For example, an embodiment including “a 10,ll,12,13,14,15,l6,l7,l8,l9 or 20 carbon atoms. It is
catalyst” should be understood to present certain aspects with an embodiment of the application that, in the alkyl groups,
one catalyst, or two or more additional catalysts. 60 one or more, including all, of the hydrogen atoms are option
In embodiments comprising an “additional” or “second” ally replaced with F or 2H and thus include, for example
component, such as an additional or second catalyst, the tri?uoromethyl, penta?uoroethyl and the like.
second component as used herein is chemically different The term “alkenyl” as used herein, whether it is used alone
from the other components or ?rst component. A “thir ” or as part of another group, means straight or branched chain,
component is different from the other, ?rst, and second com 65 unsaturated alkenyl groups. The term C2_6alkenyl means an
ponents, and further enumerated or “additional” components alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least
are similarly different. one double bond. The term Cl_20alkenyl means an alkenyl
US 8,962,841 B2
9 10
group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, The term “functionalization agent” as used herein refers to
18, 19 or 20 carbon atoms and at least one double bond. It is any compound or combination of compounds that reacts With
an embodiment of the application that, in the alkenyl groups, an N-demethylated heterocyclic compound of the invention
one or more, including all, of the hydrogen atoms are option to result in the addition of an “R2” group to the N atom,
ally replaced With E or 2H and thus include, for example Wherein R2 is as de?ned herein. In a speci?c embodiment, the
tri?uoroethenyl, penta?uoropropenyl and the like. functionalization agent is a compound of Formula III or IV as
The term “alkynyl” as used herein, Whether it is used alone de?ned herein.
or as part of another group, means straight or branched chain, As used herein, the term “acylation” and the related term
unsaturated alkynyl groups. The term C2_6alkenyl means an “acylating agent” are used in the broadest sense to encompass
alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least any reaction in Which an acyl group (a group comprising
one triple bond. The term C2_20alkenyl means an alkenyl “C(O)i”) is added to a compound. This includes reactions in
group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, Which the acyl group is derived from carboxylic acid. It also
18, 19 or 20 carbon atoms and at least one triple bond. It is an includes, for example, the addition of an acetyl group. Types
embodiment of the application that, in the alkynyl groups, one of acylating agents that may be used in the present invention
or more, including all, of the hydrogen atoms are optionally include, but are not limited to, anhydrides, dicarbonates,
replaced With E or 2H. dicarbamic agents and other known acylating agents.
The term “cycloalkyl” as used herein, Whether it is used The term “oxidant” as used herein refers to a reagent that
alone or as part of another group, means cyclic, saturated provides an oxygen species for participation in the metal
alkyl groups. The term C3_10cycloalkyl means a cycloalkyl catalyzed reactions of the present application. In an embodi
group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is an 20 ment, the oxygen source is 02 gas, air or an inorganic or
embodiment of the application that, in the cycloalkyl groups, organic peroxide (i.e. a compound comprising an “040”
one or more, including all, of the hydrogen atoms are option functionality).
ally replaced With E or 2H. t-Boc as used herein refers to the group t-butyloxycarbo
The term “cycloalkenyl” as used herein, Whether it is used nyl.
alone or as part of another group, means cyclic, unsaturated 25 Ac as used herein refers to the group acetyl.
alkyl groups. The term C3_10cycloalkenyl means a cycloalk Ts (tosyl) as used herein refers to the group p-toluenesulfo
enyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at nyl
least one double bond. It is an embodiment of the application Ms as used herein refers to the group methanesulfonyl
that, in the cycloalkenyl groups, one or more, including all, of TBDMS as used herein refers to the group t-butyldimeth
the hydrogen atoms are optionally replaced With E or 2H. 30 ylsilyl.
The term “heterocycloalkyl” as used herein, Whether it is TBDPS as used herein refers to the group t-butyldiphenyl
used alone or as part of another group, means cyclic, saturated silyl.
alkyl groups containing at least one heteroatom, such as N, O, TMS as used herein refers to the group trimethylsilyl.
and/ or S. The term C3_10cycloalkyl means a cycloalkyl group Tf as used herein refers to the group tri?uoromethanesulfo
having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in Which at least 35 nyl.
one of the carbon atoms has been replaced With a heteroatom, Ns as used herein refers to the group naphthalene sulpho
such as N, O and/ or S. It is an embodiment of the application nyl.
that, in the heterocycloalkyl groups, one or more, including Bn as used herein refers to the group benzyl.
all, of the hydrogen atoms are optionally replaced With Fmoc as used herein refers to the group ?uorenylmethoxy
E or 2H. 40 carbonyl.
The term “aryl” as used herein refers to cyclic groups that Me as used herein refers to the group methyl.
contain at least one aromatic ring. In an embodiment of the Et as used herein refers to the group ethyl.
application, the aryl group contains 6, 9 or 10 atoms, such as Ph as used herein refers to the group phenyl.
phenyl, naphthyl or indanyl. It is an embodiment of the appli Bn as used herein refers to the group benzyl.
cation that, in the aryl groups, one or more, including all, of 45 Pr as used herein refers to the group propyl.
the hydrogen atoms are optionally replaced With E or 2H and Bu as used herein refers to the group butyl.
thus include, for example penta?uorophenyl and the like. The term “leaving group” or “LG” as used herein refers to
The term “heteroaryl” as used herein refers to cyclic groups a group that is readily displaceable by a nucleophile, for
that contain at least one aromatic ring and at least one het example, under nucleophilic substitution reaction conditions.
eroatom, such as N, O and/or S. The term C5_10heteroaryl 50 Examples of suitable leaving groups include, but are not
means an aryl group having 5, 6, 7, 8, 9 or 10 atoms, in Which limited to, halo, OMs, OTs, ONs, OTf, C l_6acyl, and the like.
at least one atom is a heteroatom, such as N, O and/or S. It is The terms “protective group” or “protecting group” or
an embodiment of the application that, in the heteroaryl “PG” or the like as used herein refer to a chemical moiety
groups, one or more, including all, of the hydrogen atoms are Which protects or masks a reactive portion of a molecule to
optionally replaced With E or 2H and thus include, for 55 prevent side reactions in those reactive portions of the mol
example penta?uorophenyl and the like. ecule, While manipulating or reacting a different portion of
The term “sp2 hybridized” as used herein refers to carbon the molecule. After the manipulation or reaction is complete,
atoms that are bonded to other atoms by one double bond and the protecting group is removed under conditions that do not
two single bonds. degrade or decompose the remaining portions of the mol
The term “sp3 hybridized” as used herein refers to carbon 60 ecule. The selection of a suitable protecting group can be
atoms Where all bonds to other atoms are single bonds. made by a person skilled in the art. Many conventional pro
The term “reducing agent” as used herein means any com tecting groups are known in the art, for example as described
pound or combination of compounds that reduces a desired in “Protective Groups in Organic Chemistry” McOmie, J. F.
functional group. A reducing agent results in the overall addi W. Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G.
tion of electrons, including electrochemical addition of elec 65 M., “Protective Groups in Organic Synthesis”, John Wiley &
trons, or in the case of organic chemistry, hydrogen atoms to Sons, 3” Edition, 1999 and in Kocienski, P. Protecting
the functional group. Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Ameri
US 8,962,841 B2
11 12
cas). Examples of suitable protecting groups include, but are in the presence of a transition metal catalyst and a compound
not limited to t-Boc, Ac, Ts, Ms, silyl ethers such as TMS, of Formula III or IV:
TBDMS, TBDPS, Tf, Ns, Bn, Fmoc, benzoyl, dimethoxytri
tyl, methoxyethoxymethyl ether, methoxymethyl ether, piv RZ-LG (III)
aloyl, p-methyoxybenzyl ether, tetrahydropyranyl, trityl,
R6:C:O (IV)
ethoxyethyl ethers, carbobenzyloxy, benzoyl and the like.
The expression “proceed to a suf?cient extent” as used wherein,
herein with reference to the reactions or process steps dis R1 is selected from H, Cl_10alkyl, C(O)Cr -r oalkyl,
closed herein means that the reactions or process steps pro C(O)OCHOalkyl and PGl;
ceed to an extent that conversion of the starting material or
substrate to product is maximized. Conversion may be maxi
mized when greater than about 5, 10, 15, 20, 25, 30, 35, 40,
50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% ofthe starting
R3 is selected from H, OH, OC 1_ loalkyl, OC(O)C 1_ loalkyl,
material or substrate is converted to product.
OC(O)OC 1_ loalkyl and OPG2 or R3 is not present when the
carbon atom to which it is attached is sp2 hybridized, or R3
II. Methods of the Invention
and R5’ form a CH24CH2 linker between the carbon atoms
to which they are attached;
The present invention provides a one pot method for the
R4 is selected from H, Cl_10alkyl, C(O)C l_10alkyl, hydroxyl
N-demethylation and N-functionalization of a tertiary N-me
substituted C l_10alkyl, and PG3 -O-substituted C l_10alkyl;
thylated heterocycle comprising reacting a N-methylated het
erocycle substrate with a functionalization agent in the pres 20 R5 is selected from OH, OC l_10alkyl, OC(O)C 1_ loalkyl,
OC(O)OC 1_ loalkyl and OPG4 when the -_-; to which it is
ence of a catalyst.
attached is a single bond, or R5 is O when the E to which
In one embodiment, the present invention provides a one
it is attached is a double bond,
pot method for the N-demethylation and N-functionalization
of a tertiary N-methylated heterocycle comprising reacting a R5’ is either not present or R5 v and R3 form a CHZiCH2 linker
N-methylated heterocycle substrate with a functionalization 25 between the carbon atoms to which they are attached, only
when R5 = is Rsi and the carbon to which it is attached
agent, other than a haloformate ester, in the presence of a
is sp3 hybridized;
catalyst to obtain an N-functionalized heterocyclic derivative
R6 and R6’ are independently selected from C3_10cycloalkyl,
product. The method of the present application advanta
C3_10heterocycloalkyl, C3_locycloalkenyl, Cl_20alkyl,
geously provides the N-functionalized product at lower tem
C2_20alkenyl, C2_20alkynyl, C6_10aryl and C5_10heteroaryl,
peratures than methods reported in the literature. 30
each of the latter eight groups being unsubstituted or sub
Some of the N-functionalized heterocyclic derivative prod
stituted with one or more sub stituents independently
ucts produced using the method of the invention are morphine
selected from R7, ORS, SiR7R7'R8, NRSRsv, SR8, S(O)R7,
alkaloid derivatives, the identity of which will, of course, vary
SOzR7, halo, CN and NOZ;
with the tertiary N-methylated heterocycle substrate. Accord
ingly, the present application includes a method of preparing 35 R7 and R7’ are independently selected from C l_6alkyl,
C6_10aryl and C1_6alkyleneC6_lOaryl;
a compound of Formula I:
R8 and R8’ are independently selected from H, PGS, C l_6alkyl,
C6_10aryl and C1_6alkyleneC6_lOaryl;
: represents a single or double bond, provided that two
(I)
40 double bonds are not adjacent to each other;
PGl, PGZ, PG3 , PG4 and PG5 are independently, a protecting
group that is removable after the preparation of the com
pound of Formula I; and
LG is a leaving group,
45 wherein, when (a) R1, R8 and/or R8’ are H; (b) R3 and/ or R5 is
OH; and/or (c) R4 is hydroxyl-substituted Cl_10alkyl, the
method further comprises removal of any R2 group in R1,
R8, R8, R3, R5 and/or R4.
In an embodiment of the invention, the method of prepar
50 ing the compound of Formula I further comprises reacting the
compound of Formula II with a compound of Formula III or
IV, in the presence of a transition metal catalyst and an oxi
(ldlll.
In an embodiment of the invention R1 is selected from H,
(H) 55 C l_6alkyl, C(O)Cl_6alkyl, C(O)OC1_6alkyl and PGl. In a fur
ther embodiment, R1 is selected from H, Me, Et, C(O)Me,
C(O)Et, C(O)OMe, C(O)OEt and PGl.
In an embodiment of the invention, R2 is selected from
C(O)R6, C(O)OR6, and C(O)NR6R6'. In another embodiment
60 R2 is C(O)R6.
In an embodiment of the invention, R3 is selected from H,
OH, OC1_6alkyl, OC(O)C1_6alkyl, OC(O)OC1_6alkyl and
OPG2 or R3 is not present when the carbon atom to which it is
attached is sp2 hybridized. In another embodiment, R3 is
65 selected from H, OH, OMe, OEt, OC(O)Me, OC(O)Et,
OC(O)OMe, OC(O)OEt and OPG2 or R3 is not present when
the carbon atom to which it is attached is sp2 hybridized. In
US 8,962,841 B2
13 14
yet another embodiment R3 is selected from H, OH, OC(O) As noted above, 2 represents a single or double bond,
Me and OPG2 or R3 is not present when the carbon atom to provided that two double bonds are not adjacent to each other.
which it is attached is sp2 hybridized. In an embodiment, the -_-; bonds, R3, R4 and R5 are selected
to provide a compound of Formula II(a):
In an embodiment of the invention, R4 is selected from H,
C(O)Cl_6alkyl, hydroxyl-substituted Cl_loalkyl and PG3-O
substituted C1_ loalkyl. In another embodiment, R4 is selected
II(a)
from H, C(O)Cl_4alkyl and hydroxyl-substituted C2_8alkyl.
In yet another embodiment, R4 is selected from H, C(O)Me
and C(Me)(OH)(t-butyl).
In an embodiment of the invention, the 2 to which R5 is
attached is a single bond and R5 is selected from OH,
OC1_6alkyl, OC(O)C1_6alkyl, OC(O)OC1_6alkyl and OPG4.
In a further embodiment, the -_-; to which R5 is attached is a
single bond and R5 is selected from OH, OMe, OEt, OC(O)
Me, OC(O)Et, OC(O)OMe, OC(O)OEt and OPG4. In yet
another embodiment, the 1-; to which R5 is attached is a wherein R1 is H, Cl_10alkyl, C(O)Cl_loalkyl,
single bond and R5 is selected from OH, OMe, OC(O)Me and C(O)OC1_10alkyl or PGl (suitably H, Me, PG1 or C(O)
OPG4. In yet another embodiment of the invention, the -_-; to 20 Me); R3 is H, OH, OCl_lOalkyl, OC(O)Cl_lOalkyl, OC(O)
which R5 is attached is a double bond and R5 is O. OCl_loalkyl or OPG2 (suitably H, OC(O)Me, OPG2 or
In an embodiment of the invention R3 and R5’ form a OH); and R5 is OH, OC 1_ loalkyl, OC(O)C 1_ loalkyl, OC(O)
CH24CH2 linker between the carbon atoms to which they OC1_ loalkyl or OPG4, (suitably OH, OC(O)Me, OPG4 or
are attached. 25 OMe), when ;_-_-_ ; is a single bond and R5 is O when 1-; is
In an embodiment of the invention, R6 and R6’ are indepen a double bond;
dently selected from C3_7cycloalkyl, C3_7heterocycloalkyl, or a compound of Formula II(b)
C3_7cycloalkenyl, Cl_15alkyl, C2_15alkenyl, C2_15alkynyl,
C6_10aryl and C6_10heteroaryl, each of the latter eight groups
30 II(b)
being unsubstituted or substituted with one, two, three or four
substituents independently selected from R7, ORS, halo, CN
and NOZ. In another embodiment, R6 and R6’ are indepen
dently selected from cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, Me, Et, i-Pr, Pr, n-Bu, s-Bu, t-Bu, n-pentyl,
n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, allyl,
propargyl, and phenyl, each of these groups being unsubsti
tuted.
In an embodiment of the invention, R7 and R7’ are indepen 40
wherein R1 is H, Cl_10alkyl, C(O)Cl_loalkyl,
dently selected from Me, Et, Ph and En.
C(O)OC1_10alkyl or PGl (suitably H, Me, PG1 or C(O)
In an embodiment of the invention, R8 and R8’ are indepen Me); R3 is H, OH, OCHOalkyl, OC(O)Cl_lOalkyl, OC(O)
dently selected from H, PGS, Me, Et, Ph and En. OCl_loalkyl or OPG2 (suitably H, OC(O)Me, OPG2 or
In an embodiment of the application, PGl, PGZ, PG3, PG4 45 OH); and R5 is OH, OC 1_ loalkyl, OC(O)C 1_ loalkyl, OC(O)
OC1_ loalkyl or OPG4 (suitably OH, OPG4, OC(O)Me or
and PG5 are independently, any suitable protecting group that
OMe), when 1-; is a single bond and R5 is O when -_-; is
is removable after the preparation of the compound of For
a double bond;
mula I. The selection of a suitable protecting group will
or a compound of Formula II(c):
depend on the identity of other functional groups present in
50
the compounds, and the reaction conditions, but is within the
skill of a person in the art. For example, suitable protecting 11(0)
groups include, but are not limited to, t-Boc, Ac, Ts, Ms, silyl
ethers such as TMS, TBDMS and TBDPS, Tf, Ns, Bn, Fmoc,
benzoyl, dimethoxytrityl, methoxyethoxymethyl ether, 55
methoxymethyl ether, pivaloyl, p-methyoxybenzyl ether, tet
rahydropyranyl, trityl, ethoxyethyl ethers, carbobenzyloxy,
benzoyl and the like.
In an embodiment of the application, LG is any suitable 60
leaving group. In a further embodiment, LG also electrophili
cally activates the adjacent group for reaction with a nucleo
phile. In a further embodiment, LG is Cl, Br, CN, CCl3, wherein RI is H, CHOalkyl, C(O)Cl_loalkyl,
imidazole, penta?uorophenyl, acyl, OiR2, SiRZ, NHiRz, C(O)OC1_10alkyl or PGl (suitably H, Me, PG1 or C(O)
OTs, ONs, OMs, or any activating group, for example acti 65 Me); and R5 is OH, OCl_lOalkyl, OC(O)C1_10alkyl, OC(O)
vating groups used in peptide synthesis. In a speci?c embodi OC1_ loalkyl or OPG4, (suitably OH, OPG4, OC(O)Me or
ment, LG is C1 or OiR2. OMe);