Improved synthesis of buprenorphine from thebaine and/or oripavine via palladium-catalyzed N-demethylation/acylation and/or concomitant O-demethylation

Article abstract of DOI:10.1002/adsc.201100807

An improved preparation of buprenorphine via palladium-catalyzed N-demethylation/acylation is reported. Three routes were investigated and compared in overall yield. The first involved N-demethylation/acylation of an advanced intermediate obtained from thebaine followed by hydrolysis of the N-acetamide and alkylation with cyclopropylmethyl bromide and/or reduction of the N-acetyl group with the Schwartz reagent followed by N-alkylation. The second route employed cyclopropylcarboxylic acid anhydride in the N-demethylation/acylation protocol and subsequent reduction of the cyclopropylcarboxamide by either lithium aluminum hydride or under hydrosilylation conditions. Both of these routes originated in thebaine and therefore required O-demethylation as a final step. The third route employed an N-demethylation/acylation sequence starting from oripavine rather than thebaine, thus avoiding the O-demethylation. The routes are compared for overall efficiency and experimental and spectral data are provided for all new compounds. Copyright

Full text of DOI:10.1002/adsc.201100807

FULL PAPERS
DOI: 10.1002/adsc.201100807
Improved Synthesis of Buprenorphine from Thebaine and/or
Oripavine via Palladium-Catalyzed N-Demethylation/Acylation
and/or Concomitant O-Demethylation
Ales Machara,a Lukas Werner,a Mary Ann Endoma-Arias,a D. Phillip Cox,b
and Tomas Hudlickya,*
a
Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario
L2S 3A1, Canada
E-mail: thudlicky@brocku.ca
Noramco, Inc., 503 Carr Road, Suite 200, Wilmington, DE 19809, USA
b
Received: October 22, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100807.
Abstract: An improved preparation of buprenor- hydrosilylation conditions. Both of these routes origi-
phine via palladium-catalyzed N-demethylation/acy- nated in thebaine and therefore required O-deme-
lation is reported. Three routes were investigated thylation as a final step. The third route employed
and compared in overall yield. The first involved N- an N-demethylation/acylation sequence starting from
demethylation/acylation of an advanced intermediate oripavine rather than thebaine, thus avoiding the O-
obtained from thebaine followed by hydrolysis of the demethylation. The routes are compared for overall
N-acetamide and alkylation with cyclopropylmethyl efficiency and experimental and spectral data are
bromide and/or reduction of the N-acetyl group with provided for all new compounds.
the Schwartz reagent followed by N-alkylation. The
second route employed cyclopropylcarboxylic acid Keywords: buprenorphine synthesis; hydrosilylation;
anhydride in the N-demethylation/acylation protocol morphine alkaloids; N-demethylation; O-demethyla-
and subsequent reduction of the cyclopropylcarbox- tion; palladium-catalyzed N-demethylation/acylation;
ACHTUNGTRENNUNGamide by either lithium aluminum hydride or under Schwartz reagent
Introduction
of cyanogen bromide in order to facilitate the N-de-
methylation of an advanced intermediate. An alter-
Buprenorphine, (1), is an agent used in treating mod- nate synthesis of buprenorphine from oripavine (3),
erate to severe pain and, in combination with nalox- completed recently in our laboratories, provided a
one (as Suboxone), also in the treatment of opiate ad- somewhat shorter and more practical synthesis that
diction. The original literature synthesis originates in avoided cyanogen bromide and required only N-de-
thebaine (2) and is comprised of eight chemical trans- methylation of the corresponding quaternary salts fa-
formations[1] (Figure 1). One of these involves the use cilitated by a thiolate.[2]
Figure 1. Buprenorphine syntheses from thebaine and oripavine.
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Ales Machara et al.
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Scheme 1.
During our research on general methods of N-de- Results and Discussion
methylation that would be more environmentally
benign we have reported on the N-demethylation of The exposure of N-methylamine 6 to PdACHTNUTGRNEUNG(OAc)2 and
several morphine alkaloids by utilizing biotransforma- acetic anhydride in the presence of air or oxygen pro-
tions with fungal enzymes.[3] The N-demethylation/ vided N-acetamide 10 in excellent yield, as shown in
acylation of hydrocodone and tropane alkaloids was Scheme 2.
also accomplished via palladium catalysis that provid-
The acylation/demethylation sequence was subject-
ed N-acetylhydrocodone and other acyl derivatives in ed to some optimization. Palladium salts serve as pre-
excellent yields.[4] These methods increase the number catalysts rather than catalysts.[7] Typically, in the N-de-
of protocols for N-demethylation, such as those avail- methylation reactions the initial yellow reaction mix-
able in the recent literature and based on N-oxides.[5] ture turns dark after ~5 min of heating at the selected
The original literature synthesis of buprenorphine temperature as a consequence of generating palladi-
(1) is shown in Scheme 1. It appeared logical to at- um(0). The formation of such a precipitate is usually
tempt a shortening of this protocol by developing a the evidence of a successful reaction while the ab-
demethylation procedure starting with the advanced sence can be attributed to an unsuccessful oxidative
intermediate 6.
This intermediate, 6, should be amenable to the N- minal oxidants in the catalytic cycle. Good results
demethylation/acylation protocol and yield, after one- were obtained when Pd(acac)2 or Pd(OAc)2 were
pot hydrolysis and O-demethylation, the free amine, used as catalysts and the yield was significantly im-
which would be subjected to direct N-alkylation to proved by using Cu(OAc)2 as a co-catalyst. The
demethylation. Air and oxygen were used as the ter-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
buprenorphine (1) under conditions already known in amount of acetic anhydride, initially used as a co-sol-
the literature.[6] In this paper we report the successful vent, was eventually reduced to 10–15 equivalents. A
completion of such a protocol that led to a substantial summary of the results is presented in Table 1.
shortening of the current route to buprenorphine (1).
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Adv. Synth. Catal. 2012, 354, 613 – 626

Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine
Scheme 2.
Following the oxidative N-demethylation, acet- ysis was also accompanied by O-demethylation[10] and
amide 10 was converted to the free amine 8 by the the free amine 11 was isolated along with the N-acyl
action of the Schwartz reagent.[8] Alkylation of this O-demethylated free phenol 12 and, in some cases,
amine with cyclopropylmethyl bromide followed by accompanied also by a small amount of intermediate
the O-demethylation with sodium dodecanethiolate, a 8 (<10%).
more modern version of the original use of propane-
Several conditions were investigated in order to op-
thiol[9] in O-demethylation, furnished buprenorphine timize the concomitant O- and N-demethylations.
(1) in a four-step sequence and ~60% overall yield Acidic conditions for hydrolysis of the N-acyl group
from intermediate 5, avoiding the cyanogen bromide were avoided because of the well-known rearrange-
procedure entirely.
ment and tetrahydrofuran ring closure in buprenor-
The protocol was shortened to three steps by sub- phine derivatives.[11] The use of the Gassman–Swan
jecting N-acetamide 10 to base-catalyzed hydrolysis at method with anhydrous KOH failed and did not pro-
elevated temperature. Under these conditions hydrol- vide any secondary amine.[12] Basic hydrolysis at tem-
Table 1. Optimization of N-demethylation/acylation of intermediate 6.
Entry Conditions
Ac2O
Catalyst (mol%) Co-cat. (mol%) Amide 10 [%]
1
2
3
88 mg of 6 (0.20 mmol), dioxane, 808C, 17 h, air co-solvent Pd
88 mg of 6 (0.20 mmol), dioxane, 808C, 14 h, air co-solvent PdAHCTUNGTRENNUNG
U
none
none
CuACTHNGUTRE(NNUG OAc)2 (5)
62
62
95
88 mg of 6 (0.20 mmol), dioxane, 808C, 23 h, air 15 equiv.
Pd
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Ales Machara et al.
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Table 2. Hydrolysis of acetamide 10.
Run Substrate [mg
(mmol)]
Reagent (equiv.)
KOH [mg
(mmol)]
Digol
[mL]
Temperature Time Yield 12 Yield 11 Yield 8
[8C]
[h]
[%]
[%]
[%]
1
2
3
4
5
42 (0.09)
none
none
none
none
300 (5.35)
710 (12.65)
710 (12.65)
710 (12.65)
710 (12.65)
1
170-180
170-180
170-180
220
7
7
18
3
7
37
42
9
20
38
40
35
34
37
40
0
10
0
3
0
100 (0.21)
100 (0.21)
100 (0.21)
100 (0.21)
2.4
2.4
2.4
2.4
crown ether (0.1)
[18-C-6]
cysteamine (2)
crown ether (0.05) 710 (12.65)
[18-C-6]
170-180
6
7
100 (0.21)
100 (0.21)
710 (12.65)
2.4
2.4
170-180
170-180
7
18
48
16
30
25
0
0
8
9
10
11
12
100 (0.21)
100 (0.21)
100 (0.21)
100 (0.21)
100 (0.21)
ethanolamine (2)
dodecanethiol (3)
none
cysteamine (2)
none
300 (5.35)
300 (5.35)
300 (5.35)
300 (5.35)
180 (3.21)
1
1
1
1
1
170-180
170-180
190-200
170-180
170-180
7
7
7
7
7
15
27
11
12
23
5
0
0
0
0
0
none
none
9
25
peratures below 1508C was very slow but proper con- carboxylic acid anhydride. However, the direct N-de-
ditions for deacylation were found in the combination methylation/acylation route from 6 to 13 is more effi-
of KOH and digol at >1708C. The only hydrolysis cient and provides the same ratio of axial/equatorial
successfully performed under 1508C used the combi- amide isomers as the acylation of amine 8. Reduction
nation of KOH and ethanolamine at 1308C, which of amide 13 with lithium aluminum hydride or hydro-
produced a 35% yield of 11 and 12, indicating that silylation then furnished N-cyclopropylmethylamine
under these conditions the O-demethylation also 9.
occurs. Concentration of the substrate was found to
Optimization of the demethylation/cyclopropylcar-
be a crucial parameter as we have observed substan- boxylation was performed as well. This reaction re-
tial lowering of yield at a loading of 10% w/w of the quired higher temperature and longer reaction times
substrate. Reaction time or the presence of various than acetylation, with the optimal loading of anhy-
additives containing nucleophilic amine/thiol groups dride not lower than 7 equivalents.
did not have a pronounced effect on the yield or on
the ratio of 11 and 12 produced. A summary of the hydrosilylation protocols available in the literature.
reaction conditions is provided in Table 2. The hydrosilylation constitutes a very elegant method
The reduction was also carried out using various
Intermediate phenol 12 was easily separated by ex- of transforming amides into amines. In comparison
traction and subjected to a second-cycle hydrolysis. with standard reductions by lithium aluminum hy-
Finally, alkylation of the secondary amine 11 with cy- dride, hydrosilylation is less hazardous on large scales
clopropylmethyl bromide under previously reported and does not require potentially arduous work-up
conditions provided buprenorphine (1) in 86% yield. (i.e., aluminates). Hydroboration is also well-known
The overall yield for the three-step sequence from in- for this particular functional group interconversion
termediate 5 was 65%.
but the main drawbacks of this methodology are the
We then turned to the second-generation approach cost of borane complexes and the experimental issues
that would utilize cyclopropanecarboxylic acid anhy- in the release of the product from the boramine com-
dride. The acylating agent was prepared by reaction plex. Such drawbacks may therefore limit the applica-
of the inexpensive cyclopropylcarboxylic acid, the cor- tions of hydroboration of amides on larger (i.e., in-
responding acyl chloride, and triethylamine in a non- dustrial) scales.
polar solvent system (hexane). The precipitated tri-
ethylammonium hydrochloride was filtered off and, rather under-appreciated method of amide reduction,
after concentration of the filtrate, the product was dis- in spite of the fact that it utilizes safe and inexpensive
tilled under reduced pressure. This procedure is also reagents, such as polymethylhydrosiloxane
suitable for multigram preparation.
(PMHS).[14] Catalysts that are usually used for this
On the other hand, hydrosilylation[13] represents a
ACHTUNGTRENNUNG
We were pleased to find that under palladium catal- process are complexes of Pt, Rh, Ru or other noble
ysis and either an air or an oxygen atmosphere we metals. So-called Karstedtꢁs catalyst has attracted the
were able to produce the cyclopropylcarbonyl amide attention of chemists because of its extraordinary re-
13 from 6 in excellent yield, as shown in Scheme 3. activity and structural simplicity. In initial screening
Comparable yields (90–95%) of amide 13 were also runs the use of Karstedtꢁs catalyst in combination
attained by acylation of amine 8 with cyclopropane- with PMHS proved to be viable especially as these re-
616
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Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine
Table 3. Reduction of amide 13 to O-methylbuprenorphine 9 via hydrosilylation.
Run
Catalyst (mol%)
Silane (equiv.)[a]
Solvent
Temperature [8C]
Yield [%]
1
2
3
4
5
6
7
8
Karstedtꢁs (10)
Karstedtꢀs (10)
Karstedtꢁs (10)
Karstedtꢁs (10)
Karstedtꢀs (3)
PMHS (10)
PMHS (8)
TMDS (8)
PMHS (4+2)
PMHS (6)
PMHS (8)
Et3SiH (5)
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
60
r.t.
56[b]
84
50
76
87
78
0
Pt
InBr3 (5)
Zn(OAc)2 (15)
A
C
(EtO)3SiH (5)
THF
0
9
Cp2TiF2 (10)
PMHS (8)
PMHS (8)
PMHS (9)
PMHS (8)
Et3SiH (8)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
100
100
100
100
traces
0
14
6
0
0
24
22
72
10
11
12
13
14
15
16
17
MoO2Cl2 (10)
Ru3(CO)12 (10)
Mo(CO)6 (10)
Fe2(CO)9 (10)
Fe2(CO)9 (10)
Fe2(CO)9 (10)
Fe3(CO)12 (10)
Fe3(CO)12 (15[c])
A
TMDS (4)
TMDS (4)
PMHS (8)
[a]
The number of equivalents refers to silicon hydride equivalents not to equivalents of the polymer used.
Indicates work-up without methanolysis under basic conditions.
Indicates addition of one large portion of catalyst rather than multiple additions of smaller amounts during the reaction
[b]
[c]
actions work well at room temperature; the absence mide with triethylsilane[15] or zinc acetate[16] with tri-
of hydrolysis of the reaction mixture accounted for ethoxysilane did not lead to effective hydrosilylation
AHCTUNGTRENNUNG
[17]
the moderate yields. Work-up by methanolysis under of 13. The use of Ru3(CO)12[18] gave a low 12% yield,
basic conditions provided 9 in 87% yield from amide while MoO2Cl2 or Mo(CO)6 provided only traces of
[12a]
13.
the product. Pt
G
works well with PMHS
Other catalysts and protocols for hydrosilylation of but is more expensive than Karstedtꢁs catalyst. Other
13 were investigated as well. The use of indium bro- alternatives include difluorotitanocene[19] or iron car-
Scheme 3.
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Ales Machara et al.
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bonyl,[20] the use of the latter catalyst gave 72% yield the acyl amide 18, whose treatment with Vitride fur-
of 9 (Table 3). Of special significance, as pointed out nished buprenorphine (1) in six steps overall from ori-
by the authors, is the low cost and the “green” charac- pavine (3). The yields for each of the steps were
ter of this catalyst.
>70% and are unoptimized.
Finally, O-demethylation of 9 with sodium thiolate
In addition, we converted oripavine (3) to its O-car-
provided buprenorphine (1) in three steps from 6 in bonate 19 and converted this material to its Diels–
an overall yield of 66%. Alder adduct 20 in a slightly higher yield of 81%. Hy-
The improvements in the synthesis of buprenor- drogenation provided 16 in 84% yield. The yields of
phine (1) from thebaine (2) via the N-demethylation/ 16 are comparable for these two routes: 52% from or-
acylation protocol led us to consider a similar ap- ipavine (3) via 14 and 15 versus 55% via 19 and 20.
proach from oripavine (3) and/or its O-carbonate. We
have previously converted oripavine (3) to buprenor-
phine (1) via N-cyclopropylmethyl-nororipavine and Conclusions
the comparison of the intended route from oripavine
(3) or its carbonate would be useful. The route is de- We have provided several substantially improved
picted in Scheme 4 and begins with the conversion of routes to buprenorphine (1). The first improvement
oripavine (3) to the Diels–Alder adduct 14, the satu- was attained by the conversion of intermediate 6 [ob-
rated derivative 15, the O-carbonate 16, and the tert- tained form thebaine (2)] to buprenorphine (1) via
butyl carbinol 17 by the applications of standard pro- palladium-catalyzed N-demethylation/acylation of 6
cedures utilized with thebaine (2). The palladium-cat- followed by treatment with Schwartz reagent, N-alky-
alyzed N-demethylation of 17 in the presence of the lation, and thiolate-mediated O-demethylation to pro-
cyclopropylmethylcarboxylic acid anhydride provided vide buprenorphine (1) in four steps and 60% overall
Scheme 4.
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Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine
20.3, 18.2; MS (FAB+): m/z (%)=44 (14), 101 (17), 352
(32), 384 (36), 424 (57), 442 (100); HR-MS: m/z=442.2985,
calcd. for C27H40NO4: 442.2952.
yield from 6. The second route involved basic hydrol-
ysis of the N-acyl intermediate, which resulted in con-
comitant O-demethylation to norbuprenorphine. N-
Alkylation then provided buprenorphine (1) in 65%
overall yield. Both routes avoid the use of cyanogen
bromide employed in the original preparation of the
title compound. The third route employed the palladi-
um-catalyzed N-demethylation/acylation of 6 with cy-
clopropylcarboxylic acid anhydride, followed by re-
duction and O-demethylation. This three-step se-
quence proceeded in 66% overall yield from 6 and is
superior to the former two methods.
1-[(5a,7a)-3-Methoxy-4,5-epoxy-18,19-dihydro-7-
[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-
6,14-ethenomorphinan-17-yl]-ethanone (10)
In addition, a similar N-demethylation/acylation
protocol was applied to oripavine (3) and its O-car-
bonate 19 for a direct comparison with the sequence
from thebaine (2). Both routes from oripavine (3)
proceed in six steps with an overall yield of 25%. This
compares well with the eight-step commercial prepa-
ration from thebaine (2). Further improvements in
optimization of the route from oripavine (3) will be
realized by combining the Diels–Alder and hydroge-
nation steps in a one-pot operation. We will report on
these and other endeavors in due course.
The mixture of amine 6 (88 mg, 0.20 mmol), Pd
ACHTUNGTRENNUNG(OAc)2
(2.2 mg, 0.01 mmol), Cu(OAc)2 (2.0 mg, 0.01 mmol), acetic
AHCTUNGTRENNUNG
anhydride (300 mg, 3.0 mmol; 15 equiv.) and dioxane (1 mL)
was stirred at 808C for 23 h. Then the mixture was evaporat-
ed to a thick oil and diluted with dichloromethane (5 mL).
The resulting mixture was washed with a saturated solution
of NaHCO3 (10 mL) and the aqueous layer was extracted
with dichloromethane (3ꢂ3 mL). Combined organic layers
were washed with water, brine, dried over Na2SO4 and con-
centrated. Column chromatography (eluent EtOAc) afford-
ed acetamide 10; yield: 90 mg (95%); ratio of isomers 1:1.5;
mp 155–1598C (EtOH, mixture of isomers); Rf =0.51 (ethyl
acetate); IR (CHCl3): n=3396, 3001, 2840, 1628, 1503, 1441,
1163, 1080, 908 cmÀ1; MS (EI+): m/z (%)=43 (29), 57 (14),
84 (100), 352 (33), 380 (100), 394 (45), 412 (87), 469 (2);
HR-MS: m/z=469.2832, calcd. for C28H39NO5: 469.2828.
Major isomer: 1H NMR (600 MHz, CDCl3): d=6.77 (d,
J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 5.79 (s, 1H, OH),
4.87 (d, J=6.9 Hz, 1H), 4.44 (s, 1H), 3.90 (s, 3H), 3.64 (dd,
J=14.1, 5.1 Hz, 1H), 3.56 (s, 3H), 3.34 (ddd, J=13.4, 13.4,
3.0 Hz, 1H), 2.89 (m, 1H), 2.74 (d, J=18.7 Hz, 1H), 2.15 (s,
3H), 2.08 (m, 1H), 1.99 (m, 1H), 1.96–1.82 (m, 3H), 1.78
(m, 1H), 1.52 (dd, J=12.3, 10.0 Hz, 1H), 1.34 (s, 3H), 1.23
(m, 2H), 0.99 (s, 9H), 0.73 (m, 1H); 13C NMR (150 MHz,
CDCl3): d=168.8, 147.0, 142.1, 131.4, 127.0, 119.9, 114.6,
96.4, 80.4, 79.2, 56.8, 52.7, 49.6, 46.2, 43.9, 40.3, 38.7, 35.0,
32.9, 32.6, 32.0, 28.7, 26.4, 21.6, 20.1, 17.8.
Experimental Section
ACHTUNGTRENNUNG[5a,7a]-(1,1-Dimethylethyl)-4,5-epoxy-18,19-dihydro-
3,6-dimethoxy-a,17-dimethyl-6,14-ethenomorphinan-
7-methanol (6)
This intermediate was prepared according to literature
methods described in ref.[1]; mp 186–1888C (EtOH); Rf =
0.46 (ethyl acetate); [a]2D0: À107.2 (c 1.0, CHCl3); IR
(CHCl3): n=3384, 2980, 2840, 1630, 1502, 1453, 1130, 1080,
Minor isomer: 1H NMR (600 MHz, CDCl3): d=6.77 (d,
J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 5.80 (s, 1H, OH),
4.57 (dd, J=14.1, 5.2 Hz, 1H), 4.45 (s, 1H), 3.90 (s, 3H),
3.85 (d, J=6.6 Hz, 1H), 3.56 (s, 3H), 3.01–2.92 (m, 2H),
2.79 (m, 1H), 2.20–2.12 (m, 2H), 2.12 (s, 3H), 1.96–1.82 (m,
3H), 1.78 (m, 1H), 1.44 (dd, J=9.6, 6.6 Hz, 1H), 1.36 (s,
3H), 1.18 (m, 1H), 0.99 (s, 9H), 0.78 (m, 1H); 13C NMR
(150 MHz, CDCl3): d=168.7, 147.1, 142.2, 131.4, 126.2,
119.7, 114.8, 96.1, 80.2, 79.1, 56.9, 56.1, 52.7, 46.0, 43.4, 40.4,
36.0, 35.4, 34.1, 33.4, 32.6, 29.1, 26.4, 21.7, 20.1, 18.0.
941 cmÀ1
;
1H NMR (600 MHz, CDCl3): d=6.72 (d, J=
8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 5,96 (s, 1H, OH), 4.44
(d, J=1.4 Hz, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.13 (d, J=
18.4 Hz, 1H), 2.82 (ddd, J=13.2, 13.2, 3.8 Hz, 1H), 2.65 (d,
J=6.3 Hz, 1H), 2.44 (dd, J=11.9, 5.3 Hz, 1H), 2.31 (s, 3H),
2.29 (dd, J=12.3, 3.8 Hz, 1H), 2.23 (dd, J=18.4, 6.4 Hz,
1H), 2.17 (dd, J=9.8, 9.8 Hz, 1H), 1.99 (ddd, J=12.7, 12.7,
5.6 Hz, 1H), 1.86 (m, 1H), 1.78 (ddd, J=12.7, 12.7, 5.7 Hz,
1H), 1.69 (dd, J=12.9, 12.9, 2.6 Hz, 1H), 1.37 (s, 3H), 1.34
(dd, J=13.2, 9.1 Hz, 1H), 1.09 (m, 1H), 1.05 (s, 9H), 0.76
(m, 1H); 13C NMR (150 MHz, CDCl3): d=146.9, 141.7,
132.7, 128.9, 119.1, 114.0, 96.6, 80.6, 79.4, 61.4, 56.8, 52.6,
45.4, 45.1, 43.6, 43.5, 40.4, 36.0, 35.6, 33.4, 29.6, 26.4, 22.0,
Adv. Synth. Catal. 2012, 354, 613 – 626
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Ales Machara et al.
FULL PAPERS
reflux for 90 min. The mixture was allowed to cool and then
quenched with EtOAc (1 mL). The mixture was stirred for
15 min, then water was added (15 mg), followed by the addi-
tion of 15% w/w solution of NaOH (15 mg), and, finally, the
addition of water (43 mg) [Fieserꢁs work-up]. The resulting
suspension was stirred for 30 min, the organic supernatant
was decanted, and the precipitate was vigorously stirred in
EtOAc (10 mL). This operation was repeated four times, the
combined EtOAC extracts were evaporated to dryness, and
the residue was subjected to column chromatography
(eluent EtOAc:hexane=1:1) to afford product 9 as a white
solid; yield: 80 mg (72%).
ACHTUNGTRENNUNG
Method B: A flame-dried flask thoroughly purged with
argon was charged with amide 13 (135 mg, 0.272 mmol), tol-
À
uene (3 mL), PMHS (98 mg, 1.63 mmol of Si H bond) and
Karstedtꢁs catalyst (800 mg of approx. 2% w/w Pt solution in
xylene) was added dropwise. After 5 min gentle bubbling
decreased and the color of reaction mixture turned to
yellow. The mixture was slowly stirred for 3 h, then metha-
nol (4 mL) and NaOH (140 mg) were added. The mixture
was stirred at 808C for 2 h, then concentrated under
vacuum, and diluted with water and EtOAc. The mixture
was extracted three times with EtOAc and the combined or-
ganic layers were washed with water, brine, dried over
Na2SO4 and concentrated. Column chromatography (eluent
EtOAc:hexane=1:3) afforded the N-cyclopropylmethyl
amine 9; yield: 115 mg (87%).
To the solution of acetamide 10 (160 mg, 0.34 mmol) in
THF (4 mL) at room temperature was added Schwartzꢁs re-
agent (263 mg, 1.02 mmol) in one portion. The resulting sus-
pension was stirred under an argon atmosphere for 40 min,
at which time the suspension turned pale red. The reaction
mixture was evaporated to a thick oil which was loaded
onto a column. Chromatography (eluent dichloromethane+
10% MeOH) afforded compound 8 as a white solid; yield:
130 mg (90%); mp 169–1718C (EtOH); Rf =0.44 (dichloro-
methane +10% methanol); [a]2D0: À99.0 (c 1.0, CHCl3); IR
(CHCl3): n=3384, 2975, 2838, 1628, 1598, 1503, 1454,
1164 cmÀ1 1H NMR (600 MHz, CDCl3): d=6.74 (d, J=
;
Method C: To the solution of amine
8 (130 mg,
8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 5.94 (s, 1H, OH), 4.42
(d, J=1.7 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H), 3.00–2.92 (m,
2H), 2.92–2.88 (m, 2H), 2.79 (dd, J=13.0, 4.8 Hz, 1H), 2.65
(ddd, J=12.1, 12.1, 3.9 Hz, 1H), 2.19 (dd, J=9.9, 9.6 Hz,
1H), 1.92–1.84 (m, 2H), 1.83–1.76 (m, 2H), 1.67 (dd, J=
13.0, 3.0 Hz, 1H), 1.40 (dd, J=13.0, 9.0 Hz, 1H), 1.37 (s,
3H), 1.09 (ddd, J=12.6, 12.6, 6.1 Hz, 1H), 1.05 (s, 9H), 0.72
(dddd, J=12.6, 12.6, 3.6, 3.6 Hz, 1H); 13C NMR (150 MHz,
CDCl3): d=146.9, 141.8, 132.6, 128.8, 119.2, 114.1, 97.0, 80.5,
79.4, 56.8, 54.3, 52.6, 46.3, 43.5, 40.4, 37.1, 35.4, 35.3, 34.3,
33.2, 29.7, 26.4, 20.3, 18.4; MS (EI+): m/z (%)=43 (36), 57
(31), 338 (100), 352 (34), 370 (64), 394 (15), 409 (7), 427 (4);
HR-MS: m/z=427.2722, calcd. for C26H37NO4: 427.2723.
0.30 mmol) in N-methylpyrrolidine (2 mL) was added
NaHCO3 (30 mg, 0.37 mmol) and finally cyclopropylmethyl
bromide (61 mg, 0.46 mmol). The reaction mixture was
placed into a pre-heated oil bath at 858C and stirred for
18 h. After this time it was diluted with water (20 mL), ex-
tracted three times with EtOAc and the combined organic
layers were washed with water (2ꢂ10 mL), brine, dried over
Na2SO4 and concentrated. Column chromatography (eluent
EtOAc:hexane=1:1) afforded amine 9; yield: 130 mg
(88%); mp 65–688C (EtOH); Rf =0.65 (ethyl acetate:hex-
ane=1:1); [a]2D0: À107.5 (c 1.0, CHCl3); IR (CHCl3): n=
3389, 2981, 2958, 2839, 1630, 1502, 1454, 1129, 1057,
942 cmÀ1
;
1H NMR (600 MHz, CDCl3): d=6.70 (d, J=
8.0 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H), 5.92 (s, 1H, OH), 4.44
(s, 1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.00 (d, J=9.4 Hz, 1H),
2.98 (m, 1H), 2.90 (ddd, J=11.9, 11.9, 3.4 Hz, 1H), 2.60 (dd,
J=11.9, 5.1 Hz, 1H), 2.36 (dd, J=12.5, 5.9 Hz, 1H), 2.30
(m, 2H), 2.24 (dd, J=18.3, 6.5 Hz, 1H), 2.16 (dd, J=9.9,
9.8 Hz, 1H), 1.98 (ddd, J=12.7, 12.7, 5.6 Hz, 1H), 1.88–1.75
(m, 2H), 1.68 (dd, J=12.7, 2.2 Hz, 1H), 1.37 (s, 3H), 1.31
(dd, J=12.9, 9.5 Hz, 1H), 1.08 (m, 1H), 1.05 (s, 9H), 0.81
(m, 1H), 0.72 (m, 1H), 0.54–0.45 (m, 2H), 0.12 (m, 2H);
13C NMR (150 MHz, CDCl3): d=146.9, 141.6, 132.9, 128.9,
119.1, 114.0, 96.7, 80.8, 79.3, 59.5, 58.3, 56.8, 52.6, 46.2, 43.9,
43.7, 40.4, 35.9, 35.8, 33.4, 29.7, 26.4, 22.8, 20.1, 18.8, 9.5, 4.2,
3.3; MS (EI+): m/z (%)=43 (53), 84 (82), 108 (47), 253
(11), 366 (9), 392 (100), 424 (29), 448 (9), 481 (11); HR-MS:
m/z=481.3120, calcd. C30H43NO4: 481.3192.
ACHTUNGTRENNUNG[5a,7a(S)]-17-(Cyclopropylmethyl)-a-(1,1-
dimethylethyl)-4,5-epoxy-18,19-dihydro-3,6-
dimethoxy-a-methyl-[5a,7a(S)]-6,14-etheno-
morphinan-7-methanol (9)
Double Deprotection of Acetamide 10
Method A: To the solution of amide 13 (110 mg, 0.22 mmol)
in THF (2 mL) was added LiAlH4 (12 mg, 0.33 mmol) in
one portion at room temperature. After 5 min the resulting
reaction mixture was placed into an oil bath and stirred at
The mixture of acetamide 10 (100 mg, 0.21 mmol), KOH
(710 mg) and digol (2.4 mL) was stirred under an inert at-
mosphere at 170–1808C for 7 h. The reaction mixture was
620
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Adv. Synth. Catal. 2012, 354, 613 – 626

Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine
then quenched with water (10 mL) and the products were
extracted with dichloromethane (2ꢂ5 mL). A saturated so-
lution of NH4Cl (1.5 mL) was added to the aqueous layer,
which was extracted with dichloromethane (2ꢂ5 mL). The
addition of saturated solution of NH4Cl followed by extrac-
tion was repeated twice, the pH of water layer was strongly
basic, and the mixture turned into a suspension. TLC analy-
sis of the aqueous layer indicated that no product remained.
The combined organic layers were washed with water, brine,
dried over Na2SO4 and concentrated. The products were iso-
lated by column chromatography (eluent EtOAc to di-
chloromethane+20% MeOH), providing 12 and 11 in the
yields shown in Table 2.
ACHTUNGTRENNUNG[5a,7a]-17-Acetyl-a-(1,1-dimethylethyl)-4,5-epoxy-18,19-
dihydro-6-methoxy-a-methyl-6,14-ethenomorphinan-7-meth-
anol amide (12): mp >2408C (MeOH); Rf =0.45 (ethyl ace-
1H), 2.26–2.10 (m, 2H), 1.97–1.78 (m, 2H), 1.55 (m, 1H),
1.37 (s, 3H), 1.27 (m, 1H), 1.18 (m, 1H), 1.09 (s, 9H), 0.88
(m, 1H), 0.76 (m, 1H); 13C NMR (150 MHz, DMSO): d=
146.2, 139.6, 131.0, 124.1, 120.2, 118.1, 93.8, 80.2, 79.1, 53.0,
52.5, 44.8, 41.9, 40.5, 35.7, 34.2, 31.7, 31.6, 29.6, 28.7, 26.7,
20.5, 18.7; MS (EI+): m/z (%)=43 (70), 57 (60), 324 (100),
338 (75), 356 (45), 381 (22), 395 (13), 413 (6); HR-MS:
m/z=413.2572, calcd. for C25H35NO4: 413.2566.
[O-Methylnorbuprenorphine cyclopropylcarbox-
amide], [5a,7a(R)]-17-(Cyclopropylcarbonyl)-a-(1,1-
dimethylethyl)-4,5-epoxy-18,19-dihydro-3,6-
dimethoxy-6,14-ethenomorphinan-7-methanol (13)
tate); IR (CHCl3): n=3583, 3390, 3000, 2981, 2876, 1626,
1504, 1457, 1370, 1310, 1159, 1090 cmÀ1; ratio of isomers
1:1.5; HR-MS: m/z=455.2663, calcd. for C27H37NO5:
455.2672.
Major isomer: 1H NMR (600 MHz, CDCl3): d=6.77 (d,
J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 5.81 (s, 1H, OH),
4.87 (d, J=7.1 Hz, 1H), 4.46 (s, 1H), 3.65 (dd, J=14.2,
5.5 Hz, 1H), 3.55 (s, 3H), 3.36 (ddd, J=13.5, 13.5, 3.8 Hz,
1H), 2.88 (m, 1H), 2.74 (d, J=18.6 Hz, 1H), 2.17 (s, 3H),
2.09 (m, 1H), 1.99 (m, 1H), 1.94–1.75 (m, 5H), 1.54 (dd, J=
13.1, 9.2 Hz, 1H), 1.34 (s, 3H), 1.25–1.19 (m, 1H), 0.99 (s,
9H), 0.76–0.69 (m, 1H); 13C NMR (150 MHz, CDCl3): d=
169.0, 145.7, 138.0, 131.1, 126.2, 120.2, 117.3, 96.66, 80.4,
79.4, 52.7, 49.7, 46.4, 43. 8, 40.3, 38.8, 35.5, 34.9, 32.6, 32.1,
28. 6, 26.4, 21.6, 20.1, 17.8.
The mixture of intermediate
6
(88 mg, 0.20 mmol),
Cu(OAc)2 (2 mg,
Pd(OAc)2 (2.2 mg, 0.01 mmol),
G
ACHTUNGTRENNUNG
0.01 mmol), cyclopropylcarboxylic acid anhydride (210 mg,
1.40 mmol) and dioxane (1 mL) was stirred under an oxygen
atmosphere at 1008C for 39 h. Then the mixture was evapo-
rated to a thick oil and diluted with dichloromethane
(10 mL). The resulting mixture was washed with a saturated
solution of NaHCO3 (10 mL) and after separation the aque-
ous layer was extracted with dichloromethane (3ꢂ5 mL).
Combined organic layers were washed with water, brine,
dried over Na2SO4 and concentrated. Column chromatogra-
phy (eluent EtOAc:hexane=1:1) afforded amide 13; yield:
98 mg (95%); ratio of isomers 1:1.5; mp 103–1058C
(MeOH, mixture of isomers); Rf =0.70 (ethyl acetate); IR
(CHCl3): n=3397, 3002, 2957, 2841, 1628, 1503, 1453, 1440,
1162, 944 cmÀ1; MS (EI+): m/z (%)=41 (68), 56 (55), 69
(100), 86 (89), 124 (19), 167 (15), 406 (29), 438 (25), 495 (1);
HR-MS: m/z=495.2990, calcd. for C30H41NO5: 495.2985.
Major isomer: 1H NMR (600 MHz, CDCl3): d=6.76 (d,
J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 5.77 (s, 1H), 4.85
(d, J=7.1 Hz, 1H), 4.44 (s, 1H), 4.06 (dd, J=14.1, 5.0 Hz,
1H), 3.89 (s, 3H), 3.55 (s, 3H), 3.38 (ddd, J=13.7, 13.7,
3.6 Hz, 1H), 2.91 (m, 1H), 2.77 (d, J=18.6, 1H), 2.06 (dd,
J=9.8, 9.8 Hz, 1H), 2.01–1.92 (m, 2H), 1.92–1.81 (m, 3H),
1.77 (m, 1H), 1.47 (d, J=12.6, 1H), 1.32 (s, 3H), 1.20 (m,
1H), 1.10 (m, 1H), 0.97 (s, 9H), 0.86 (m, 1H), 0.73–0.83 (m,
Minor isomer: 1H NMR (600 MHz, CDCl3): d=6.78 (d,
J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 5.81 (s, 1H, OH),
4.57 (dd, J=13.9, 5.6 Hz, 1H), 4.46 (s, 1H), 3.85 (d, J=
6.8 Hz, 1H), 3.56 (s, 3H), 3.00–2.88 (m, 2H), 2.81 (ddd, J=
13.4, 13.4, 4.0 Hz, 1H), 2.15 (m, 2H), 2.13 (s, 3H), 1.94–1.75
(m, 5H), 1.44 (m, 1H), 1.36 (s, 3H), 1.19–1.14 (m, 1H), 0.99
(s, 9H), 0.81–0.76 (m, 1H); 13C NMR (150 MHz, CDCl3):
d=168.9, 145.7, 138.1, 131.1, 125.4, 120.1, 117.4, 96.3, 80.3,
79.3, 56.1, 52.7, 46.3, 43.3, 40.4, 36.1, 33.9, 33. 6, 32.8, 32.7,
29.0, 26.4, 21.7, 20.1, 18.0; MS (+EI) m/z (%): 43 (100), 57
(48), 84 (82), 366 (68), 380 (78), 398 (51), 423 (6), 455 (3).
Norbuprenorphine (11): mp 227–2308C (EtOH); Rf =
0.24 (DCM+20% methanol); [a]2D0: À80.1 (c 1.0, MeOH);
IR (CHCl3): n=3587, 3397, 2957, 2848, 1598, 1460,
1124 cmÀ1 1H NMR (600 MHz, CDCl3): d=6.79 (d, J=
;
8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 5.75 (s, 1H, OH), 4.49
(s, 1H), 3.55 (s, 3H), 3.52 (m, 1H), 3.33 (m, 1H), 3.21 (m,
1H), 3.07 (m, 1H), 2.93 (dd, J=18.8, 6.3 Hz, 1H), 2.85 (m,
Adv. Synth. Catal. 2012, 354, 613 – 626
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Ales Machara et al.
FULL PAPERS
2H), 0.70 (m, 1H); 13C NMR (150 MHz, CDCl3): d=171.8,
147.1, 142.7, 131.5, 127.1, 119.9, 114.6, 96.5, 80.4, 79.1, 56.8,
52.7, 50.1, 46.5, 44.1, 40.3, 37.8, 35.8, 35.4, 32.6, 31.9, 28.7,
26.4, 19.9, 17.8, 11.1, 7.9, 6.6.
2188C (MeOH); Rf =0.23 (EtOAc:hexane=1:2); [a]2D0:
À104.2 (c 1.0, CHCl3); IR (CHCl3): n=3583, 3389, 2982,
2952, 2815, 1633, 1503, 1370, 1132; 1H NMR (600 MHz,
CDCl3): d=6.69 (d, J=8.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H),
6.01 (s, 1H), 5.46 (bs, 1H), 4.47 (d, J=1.2 Hz, 1H), 3.54 (s,
3H), 3.00 (bs, 1H), 2.99 (d, J=13.4 Hz, 1H), 2.90 (m, 1H),
2.62 (dd, J=11.9, 5.1 Hz, 1H), 2.37 (dd, J=12.6, 6.0 Hz,
1H), 2.40–2.27 (m, 2H), 2.23 (dd, J=18.3, 6.5 Hz, 1H), 2.17
(dd, J=9.8, 9.8 Hz, 1H), 1.99 (ddd, J=12.6, 12.6, 5.6 Hz,
1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.69 (dd, J=12.8, 2.5 Hz,
1H), 1.38 (s, 3H), 1.32 (dd, J=18.9, 9.2 Hz, 1H), 1.08 (m,
1H), 1.05 (s, 9H), 0.81 (m, 1H), 0.72 (m, 1H), 0.52–0.45 (m,
2H), 0.13 (m, 2H); 13C NMR (150 MHz, CDCl3): d=145.5,
137.3, 132.6, 128.3, 119.6, 116.4, 97.0, 80.9, 79.7, 59.5, 58.3,
52.6, 46.5, 43.7, 43.7, 40.4, 36.0, 35.7, 33.4, 29.6, 26.4, 22.9,
20.1, 18.2, 9.5, 4.2, 3.3; MS (EI+): m/z (%)=55 (100), 71
(64), 149 (26), 366 (21), 378 (92), 410 (31), 435 (20), 449
(23), 467 (25); HR-MS: m/z=467.3043, calcd. for
C29H41NO4: 467.3036.
Minor isomer: 1H NMR (600 MHz, CDCl3): d=6.77 (d,
J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 5.80 (s, 1H), 4.54
(dd, J=14.0, 5.3 Hz, 1H), 4.44 (s, 1H), 4.29 (d, J=6.6 Hz,
1H), 3.89 (s, 3H), 3.55 (s, 3H), 3.02 (dd, J=18.5, 6.8 Hz,
1H), 2.94 (m, 1H), 2.84 (ddd, J=13.6, 13.6, 3.9 Hz, 1H),
2.19 (ddd, J=11.8, 11.8, 3.7 Hz, 1H), 2.13 (dd, J=9.7,
9.6 Hz, 1H), 1.92–1.81 (m, 3H), 1.81–1.70 (m, 3H), 1.46 (d,
J=12.6, 1H), 1.35 (s, 3H), 1.18 (m, 1H), 1.07–0.98 (m, 2H),
0.98 (s, 9H), 0.73–0.83 (m, 3H); 13C NMR (150 MHz,
CDCl3): d=171.8, 147.0, 142.2, 131.6, 126.5, 119.7, 114.7,
96.1, 80.3, 79.1, 56.9, 55.0, 52.7, 46.2, 43.4, 40.4, 36.2, 34.1,
34.1, 33.0, 32.8, 29.2, 26.3, 20.1, 18.1, 11.1, 7.7, 7.4.
Buprenorphine (1)
Cyclopropanecarboxylic Acid Anhydride
To the solution of cyclopropylcarboxylic acid (15.15 g, 0.176
mol), dichloromethane (200 mL) and hexane (100 mL) was
added triethylamine (18.69 g, 0.185 mol) dropwise while the
flask was placed into an ice bath. After one hour cyclopro-
pylcarboxylic acid chloride (18.40 g, 0.176 mol) was added
dropwise over 10 min. The addition resulted in a thick sus-
pension of triethylammonium hydrochloride. The mixture
was vigorously stirred at room temperature for 2 h and then
the precipitate was filtered off. The filtration cake was
washed with hexane and the combined filtrates were con-
centrated under reduced pressure to approx. 50 mL volume.
Any additional precipitate was again filtered off and the
cake was washed with hexane. The solvent was removed
under reduce pressured and the residue was distilled under
high vacuum. The product was collected in two fractions
[4.19 g (65–728C/0.7 Torr) and 19.35 g (72–738C/0.7 Torr)];
overall yield: 86%.
Method A: To the solution of secondary amine 11 (70 mg,
0.17 mmol) in N-methylpyrrolidine (1 mL) was added
NaHCO3 (17 mg, 0.20 mmol) and cyclopropylmethyl bro-
mide (34 mg, 0.25 mmol). The reaction mixture was placed
into a pre-heated oil bath at 808C and stirred over 18 h. It
was then diluted with water (10 mL), extracted three times
with EtOAc, and the combined organic layers were washed
with water (2ꢂ5 mL), brine, dried over Na2SO4 and concen-
trated. Column chromatography (eluent EtOAc:hexane/1:2)
afforded buprenorphine (1); yield: 68 mg (86%).
1-[(5a,7a}-4,5-Epoxy-3-hydroxy-6-methoxy-17-
methyl-6,14-ethenomorphinan-7-yl]ethanone (14)
Method B: To DMSO (1.1 mL) thoroughly purged with
nitrogen was added freshly prepared NaOEt (97 mg,
1.43 mmol) and tert-dodecanethiol (290 mg, 1.43 mmol). A
suspension formed and was again purged with nitrogen.
After 5 min the reaction mixture was placed into an oil bath
pre-heated to 1458C. When the solid dissolved, indicating
that the thiolate formation was complete, a solution of inter-
mediate 9 (230 mg, 0.48 mmol) in DMSO (1.1 mL) was
added over 2 min. After 2 h the reaction mixture was al-
lowed to cool down, diluted with water (10 mL), and the pH
was adjusted to approx. 2 by addition of 6M HCl. This mix-
ture was washed twice with hexane (2ꢂ2 mL) and finally
the pH of the aqueous layer was adjusted to approx. 8. A
white precipitate formed and the mixture was extracted with
EtOAc, the pH was again adjusted to approx. 8–9, and the
product was extracted with EtOAc. The operation involving
the pH adjustment and subsequent extraction was repeated
once more. Combined organic layers were washed with
water (2ꢂ5 mL), brine, dried over Na2SO4 and concentrat-
ed. Column chromatography (eluent EtOAc:hexane=1:2)
afforded buprenorphine (1); yield: 180 mg (80%); mp 217–
Oripavine (2.00 g, 6.68 mmol) was suspended in toluene
(40 mL) and methyl vinyl ketone (10.80 mL, 133.60 mmol)
was added and the reaction mixture was stirred at 808C for
18 h. The resulting solution was concentrated using rotary
evaporation and the crude mixture was chromatographed on
silica gel using dichloromethane/methanol (10:1) as eluent
to afford 14 as a white solid; yield: 1.84 g (75%); mp 214–
2168C (CH2Cl2/hexane); [a]2D0: À340.2 (c 1.3, CH2Cl2); Rf =
622
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Adv. Synth. Catal. 2012, 354, 613 – 626

Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine
0.32 (10:1 CH2Cl2/MeOH); IR (CHCl3): v=3374, 3051,
1-[(5a,7a)-4,5-Epoxy-3-[(ethoxycarbonyl)oxy]-18,19-
dihydro-6-methoxy-17-methyl-6,14-ethanomorphinan-
7-yl]-ethanone (16)
2932, 2839, 2799, 1698, 1632, 1608, 1501, 1456, 1355, 1229,
1
1155, 1025, 734 cmÀ1; H NMR (300 MHz, CDCl3): d=6.62
(d, J=8.1 Hz, 1H), 6.50 (d, J=8.1 Hz, 1H), 5.87 (d, J=
8.6 Hz, 1H), 5.54 (d, J=8.6 Hz, 1H), 5.40 (s, 1H), 4.61 (s,
1H), 3.57 (s, 3H), 3.20–3.26 (m, 2H), 2.91–2.99 (m, 2H),
2.55 (dd, J=12.0, 4.8 Hz, 1H), 2.41–2.47 (m, 2H), 2.35 (s,
3H), 2.14 (s, 3H), 1.94–2.06 (m, 1H), 1.85 (dd, J=12.0,
2.4 Hz, 1H), 1.38 (dd, J=16.8, 10.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=209.0, 146.6, 137.6, 135.9, 133.7, 127.6,
125.9, 119.9, 116.5, 94.9, 81.2, 59.9, 53.1, 50.5, 47.7, 45.5, 43.5,
43.3, 33.3, 30.3, 30.30, 22.5; MS (EI+): m/z (%)=367 (50),
324 (20), 241 (40), 215 (45), 43 (100); HR-MS (EI+): m/z=
367.1787, calcd. for C22H25NO4: 367.1784; anal. calcd. for
C22H25NO4: C 71.91, H 6.86; found C 71.91, H 6.80.
A. Oripavine route: To a suspension of intermediate 15
(1.55 g, 4.19 mmol) in warm toluene (30 mL, 408C) was
added ethyl chloroformate (527 mL, 5.48 mmol) and triethyl-
amine (941 mL, 6.72 mmol). Upon addition of triethylamine
most of the solid dissolved and the reaction mixture turned
yellowish in color. TLC (silica gel, CH2Cl2/MeOH=10:1) in-
dicated the completion of reaction after 30 min. The warm
reaction mixture was filtered through a short pad of Celite
to remove triethylamine hydrochloride. The filtration bed
was washed with dichloromethane (2ꢂ50 mL). The com-
bined filtrate and washings were concentrated using rotary
evaporation to afford the crude product. It was further puri-
fied by flash column chromatography on silica gel using di-
chloromethane/methanol (10:1) as eluent to afford 16 as a
yellowish viscous oil; yield: 1.52 g (82%).
1-[(5a,7a)-4,5-Epoxy-18,19-dihydro-3-hydroxy-6-
methoxy-17-methyl-6,14-ethenomorphinan-7-yl]-
ethanone (15)
B. Oripavine carbonate route: Intermediate 20 (45 mg,
0.10 mmol), tartaric acid (17 mg, 0.01 mmol) and Pd/C
(7 mg, 10 wt%) were suspended in distilled water (1.0 mL).
The flask was then evacuated/refilled with hydrogen gas and
subjected to atmospheric hydrogenation at 808C for 2 h.
TLC analysis (silica gel, 10:1 CH2Cl2/MeOH) indicated the
consumption of starting material. The reaction mixture was
allowed to cool down to room temperature and filtered
throuh a pad of Celite to remove the catalyst. An additional
5 mL of distilled water were used to wash the Celite to re-
cover residual product. The pH of the filtrate was adjusted
to 8 using saturated sodium bicarbonate solution. The result-
ing cloudy solution was extracted with EtOAc (4ꢂ10 mL).
The combined organic extracts were dried over MgSO4, fil-
tered and concentrated to afford 16 as a yellowish oil; yield:
38 mg (84% yield); [a]D20: À208.6 (c 1.1, EtOAc); Rf =0.48
(10:1; CH2Cl2/MeOH); IR (CHCl3): v=2931, 2841, 2797,
Intermediate 14 (1.84 g, 5.01 mmol), tartaric acid (803 mg,
5.03 mmol) and Pd/C (503 mg, 10 wt%) were suspended in
distilled water (17 mL). The flask was then evacuated/re-
filled with hydrogen gas and subjected to atmospheric hy-
drogenation at 808C for 16 h. TLC analysis (silica gel, 10:1
CH2Cl2/MeOH) indicated the consumption of starting mate-
rial. The reaction mixture was allowed to cool down to
room temperature and filtered through a pad of Celite to
remove the catalyst. The pH of the filtrate was adjusted to 8
using saturated sodium bicarbonate solution. The resulting
solution was extracted with EtOAc (4ꢂ30 mL). The com-
bined organic extracts were dried over MgSO4, filtered and
concentrated to afford 15 as a yellowish solid; yield: 1.55 g
(84%); mp 198–2008C (CH2Cl2/hexane); [a]2D0: À149.6 (c 1.0,
CH2Cl2); Rf =0.76 (100:20:1; CH2Cl2/MeOH/HOAc); IR
(CHCl3): v=3327, 2929, 2838, 2799, 1707, 1608, 1502, 1457,
1
1354, 1172, 1159, 1092, 1028, 731 cmÀ1; H NMR (300 MHz,
1
1763, 1709, 1450, 1243, 1201, 1163, 1094, 759 cmÀ1; H NMR
CDCl3): d=6.72 (d, J=8.1 Hz, 1H), 6.56 (d, J=8.1 Hz, 1H),
5.32 (s, 1H), 4.51 (s, 1H), 3.43 (s, 3H), 3.03–3.14 (m, 2H),
2.64–2.76 (m, 2H), 2.48 (dd, J=12.0, 5.7 Hz, 1H), 2.24–2.38
(m, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.01–2.11 (td, J=12.0,
5.7, 1H), 1.44–1.70 (m, 4H), 1.26–1.36 (m, 1H), 0.73 (m,
1H); 13C NMR (75 MHz, CDCl3): d=210.6, 145.3, 137.4,
132.1, 128.1, 119.7, 116.6, 94.5, 77.7, 61.3, 52.0, 49.3, 46.0,
45.3, 43.5, 35.7, 35.0, 33.6, 30.4, 28.5, 22.1, 17.7; MS (EI+):
m/z=(%): 369 (30), 354 (15), 326 (20), 176 (10), 43 (100);
HR-MS (EI+): m/z=369.1936, calcd. for C22H27NO4:
369.1940.
(300 MHz, CDCl3): d=6.90 (d, J=8.4 Hz, 1H), 6.64 (d, J=
8.4 Hz, 1H), 4.51 (s, 1H), 4.29 (q, J=6.9 Hz, 2H), 3.38 (s,
3H), 3.14 (d, J=18.6 Hz, 1H), 3.00 (dd, J=10.2, 6.3 Hz,
1H), 2.75 (d, J=6.3 Hz, 1H), 2.61–2.71 (m, 1H), 2.49 (dd,
J=12.0, 5.7 Hz, 1H), 2.27–2.35 (m, 2H), 2.31 (s, 3H), 2.27
(s, 3H), 2.04 (dt, J=12.0, 5.7 Hz, 1H), 1.49–1.76 (m, 4H),
1.36 (t, J=6.9 Hz, 3H), 1.21–1.30 (m, 1H), 0.71 (m, 1H);
13C NMR (75 MHz, CDCl3): d=210.7, 153.2, 149.5, 134.5,
133.5, 132.0, 121.9, 119.3, 96. 6, 77.5, 64.9, 61.8, 52.4, 49.9,
45.9, 45.1, 43.5, 35.5, 34.7, 33.9, 30.3, 28.5, 22.5, 16.6, 14.2;
MS (EI+): m/z (%)=441 (10), 398 (5), 353 (5), 310 (5), 105
(15), 71 (55), 43 (100); HR-MS (EI+): m/z=441.2156,
calcd. for C25H31NO6: 441.2151.
Adv. Synth. Catal. 2012, 354, 613 – 626
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FULL PAPERS
ACHTUNGTRENNUNG
(silica gel, CH2Cl2/MeOH=10:1). The solvent was removed
using rotary evaporation and the residue was chromato-
graphed on silica gel using EtOAc/hexanes (4:1) as eluent to
afford 18 as a yellow solid (a mixture of isomers); yield:
800 mg (80%); ratio of isomers 1:1.5; mp 238–2398C
(EtOAc/hexane, mixture of isomers); [a]2D0: À58.3 (c 0.5,
CH2Cl2); Rf =0.67 (10:1; CH2Cl2/MeOH); IR (CHCl3): v=
3436, 2979, 1762, 1634, 1450, 1369, 1207, 1162, 1078,
734 cmÀ1; MS (FAB+): m/z=(%) 554 (30), 536 (15), 496
(15), 83 (20), 69 (100), 55 (50), 41 (75); HR-MS (FAB+):
m/z=554.3118, calcd. for C29H42NO6: 554.3226.
A solution of intermediate 16 (1.13 g, 2.57 mmol) in toluene
(23 mL) was added dropwise to a vigorously stirred suspen-
sion of tert-butylmagnesium chloride in cyclohexane/THF
(3:1) (22 mL, 1M suspension) at room temperature. After
30 min of stirring TLC analysis showed disappearance of
starting material. The reaction was quenched by careful ad-
dition of ice-water (45 mL). The organic layer was separated
from the aqueous layer, which was neutralized with a satu-
rated solution of NH4Cl to pH 7–8, then extracted with
EtOAc (3ꢂ35 mL). The combined organic extracts were
dried over MgSO4, filtered and concentrated using rotary
evaporation. The crude extract was subjected to silica gel
column chromatography using dichloromethane/methanol
(10:1) as eluent to afford 17 as a white solid; yield: 900 mg
(71%); mp 125–1278C (CH2Cl2/hexane); [a]2D0: À180.4 (c 1.2,
CH2Cl2); Rf =0.58 (10:1; CH2Cl2/MeOH); IR (CHCl3): v=
3434, 2954, 2844, 2797, 2772, 1761, 1613, 1490, 1450, 1368,
Major isomer: 1H NMR (600 MHz, CDCl3): d=6.96 (d,
J=7.8 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 5.79 (s, 1H), 4.89
(d, J=7.2 Hz, 1H), 4.49 (s, 1H), 4.30 (q, J=7.2 Hz, 2H),
4.10 (dd, J=5.4, 14.4 Hz, 1H), 3.51 (s, 3H), 3.38 (ddd, J=
13.8, 13.8, 3.6 Hz, 1H), 2.96 (m, 1H), 2.83 (d, J=19.2, 1H),
2.05 (dd, J=10.2 Hz, 1H), 1.90–1.75 (m, 5H), 1.49 (d, J=
13.2, 1H), 1.37 (t, J=7.2 Hz, 3H), 1.33 (s, 3H), 1.20 (m,
1H), 1.10 (m, 1H), 0.98 (s, 9H), 0.87 (m, 1H), 0.81–0.0.75
(m, 2H), 0.69 (m, 1H); 13C NMR (150 MHz, CDCl3): d=
171.9, 153.1, 149.9, 133.1, 132.7, 132.3, 122.6, 119.9, 97.9,
80.3, 79.1, 65.1, 52.7, 49.9, 46.5, 44.4, 40.3, 37.7, 35.9, 33.7,
32.9, 32.5, 28.7, 26.4, 19.9, 17.3, 14.2, 11.1, 8.0, 6.7.
1308, 1251, 1203, 960, 876, 737 cmÀ1 1H NMR (300 MHz,
;
Minor isomer: 1H NMR (600 MHz, CDCl3): d=6.97 (d,
J=7.8 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 5.83 (s, 1H), 4.58
(dd, J=13.8, 4.8 Hz, 1H), 4.49 (s, 1H), 4.30 (m, 1H), 4.30
(q, J=7.2 Hz, 2H), 3.52 (s, 3H), 3.04 (dd, J=18.6, 6.6 Hz,
1H), 2.97 (m, 1H), 2.85 (m, 1H), 2.21 (ddd, J=11.7, 3.8 Hz,
1H), 2.12 (dd, J=9.8, 9.7 Hz, 1H), 1.95–1.75 (m, 4H), 1.48
(d, J=12.6 Hz, 1H), 1.37 (t, J=7.2 Hz, 3H), 1.33 (s, 3H),
1.13 (m, 1H), 1.08–0.98 (m, 2H), 0.99 (s, 9H), 0.80–0.70 (m,
3H); 13C NMR (150 MHz, CDCl3): d=171.9, 153.1, 149.9,
133.1, 132.7, 132.4, 122.7, 119.8, 97.7, 80.2, 79.1, 65.1, 54.8,
52.7, 46.4, 43.8, 40.4, 36.3, 35.0, 34.0, 33.2, 32.3, 29.3, 26.3,
20.0, 17.4, 14.2, 11.2, 7.8, 7.5.
CDCl3): d=6.90 (d, J=8.1 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H),
5.96 (s, 1H), 4.47 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.51 (s,
3H), 3.16 (d, J=18.9 Hz, 1H), 2.82 (td, J=11.1, 3.9 Hz,
1H), 2.68 (d, J=6.3 Hz, 1H), 2.46 (dd, J=11.1, 4.8 Hz, 1H),
2.28 (s, 3H), 2.21–2.24 (m, 2H), 2.14 (t, J=9.3 Hz, 1H),
1.85–2.05 (m, 3H), 1.73 (dd, J=12.9, 2.4 Hz, 1H), 1.57 (s,
1H), 1.37 (s, 3H), 1.37 (t,J=7.2 Hz, 3H), 1.31–1.39 (m, 1H),
1.05 (s, 9H), 0.68–0.76 (m, 1H); 13C NMR (75 MHz,
CDCl3): d=153.2, 149.6, 134.8, 133.8, 131.9, 121.8, 119.3,
98.2, 80.6, 79.3, 64.9, 61.2, 52.6, 45.5, 45.0, 44.0, 43.6, 40.4,
36.0, 35.2, 33.3, 29.7, 26.4, 22.4, 20.1, 17.5, 14.2; MS (EI+):
m/z (%)=499 (5), 442 (20), 84 (20), 41 (100); HR-MS
(EI+): m/z=499.2927, calcd. for C29H41NO6: 499.2934; anal.
calcd. for C29H41NO6: C 69.71, H 8.27; found C 69.82, H
8.27.
[5a]-6,7,8,14-Tetradehydro-4,5-epoxy-3-[(ethoxy-
carbonyl)oxy]-6-methoxy-17-methylmorphinan-3-ol
(19)
ACHTUNGTRENNUNG[5a,7a(S)]-17-(Cyclopropylcarbony)-a-(1,1-
dimethylethyl)-4,5-epoxy-3-[(ethoxycarbonyl)oxy]-
18,19-dihydro-6-methoxy-a-methyl-6,14-etheno-
morphinan-7-methanol (18)
Intermediate 16 (900 mg, 1.80 mmol), cyclopropylcarboxylic
acid anhydride (2.70 g, 18.00 mmol), Pd
ACHTUNGRTENUN(NG OAc)2 (20 mg,
0.09 mmol), and Cu(OAc)2 (18.0 mg, 0.09 mmol) were sus-
AHCTUNGTRENNUNG
To a suspension of oripavine (1) (0.10 g, 0.33 mmol) in
CH2Cl2 (3 mL) was added diethyl pyrocarbonate (0.081 g,
0.50 mmol), followed by a catalytic amount of N,N-dimethyl-
aminopyridine (2.0 mg, 0.02 mmol). A vigorous evolution of
pended in dioxane (18 mL). The reaction vessel was three
times evacuated/refilled with O2 gas. Then it was subjected
to an atmosphere of O2 gas while stirring at 808C for 12 h.
TLC analysis indicated disappearance of starting material
624
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 613 – 626

Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine
gas was observed upon addition of catalyst with a concomi-
tant dissolution of oripavine. The reaction mixture was
stirred at room temperature until the disappearance of start-
ing material as monitored by TLC. After 1 h the reaction
was complete by TLC. The reaction mixture was diluted
with CH2Cl2 (10 mL), washed with 1N HCl (3 mL) and with
saturated NaHCO3 (3 mL). The organic extract was dried
over Na2SO4, filtered, and concentrated by rotary evapora-
tion. The crude mixture was purified by chromatography on
silica gel with CH2Cl2/MeOH (10:1) as eluent to afford ori-
pavine O-carbonate 19 as a colorless viscous oil; yield:
100 mg (81%); [a]2D0: À113.7 (c 2.1, CH2Cl2); Rf =0.56 (10:1;
CH2Cl2/MeOH); IR (film): v=3401, 2932, 2839, 2800, 1765,
1670, 1607, 1493, 1446, 1369, 1242, 1200, 1144, 1020, 866,
33.1, 30.8, 29.8, 22.9, 14.2; MS (EI+): m/z (%)=439 (11),
206 (29), 130 (24), 84 (100), 58 (39), 43 (37); HR-MS (EI+):
m/z=439.1995, calcd. for C25H29NO6: 439.1995.
Buprenorphine (1)
731 cmÀ1 1H NMR (300 MHz , CDCl3): d=6.85 (d, J=
;
8.1 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.58 (d, J=6.6 Hz,
1H), 5.34 (s, 1H), 5.06 (d, J=6.6 Hz, 1H), 4.31 (q, J=
7.2 Hz, 2H), 3.62–3.65 (m, 4H), 3.34 (d, J=18.3 Hz, 1H),
2.82 (ddd, J=12.9, 12.9, 3.6 Hz, 1H), 2.74 (dd, J=18.3,
6.9 Hz, 1H), 2.66 (m, 1H), 2.47 (s, 3H), 2.22 (ddd, J=12.6,
12.6, 5.4 Hz, 1H), 1.78 (dd, J=12.6, 2.1 Hz, 1H), 1.37 (t, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=153.2, 152.3,
147.6, 134.5, 133.4, 132.8, 132.0, 121.5, 119.3, 111.8, 96.3,
89.9, 64.9, 60.6, 55.1, 46.0, 45.9, 42.4, 36.8, 29.9, 14.1; MS
(EI+): m/z (%)=369 (6), 323 (17), 119 (10), 88 (15), 86
(85), 84 (100), 47 (23), 42 (14); HR-MS (EI+): m/z=
369.1576, calcd. for C21H23NO5: 369.1576.
Intermediate 18 (800 mg, 1.34 mmol) in THF (10 mL) was
added to Vitride (10 mL, 10 wt% in toluene) at room tem-
perature. A vigorous bubbling was observed. The resulting
mixture was heated to 808C for 30 min. To the reaction mix-
ture cooled down to room temperature was added Ro-
chelleꢁs salt (15 mL). The resulting suspension was extracted
with Et2O (3ꢂ15 mL). The combined extracts were dried
over Na2SO4, filtered and concentrated using rotary evapo-
ration. The residue was purified by flash column chromatog-
raphy on silica gel using hexanes/EtOAc (1:1) as eluent to
afford buprenorphine (1) as a white solid; yield: 550 mg
(81%).
1-[5a,7a(S)]-4,5-Epoxy-3-[(ethoxycarbonyl)oxy]-
18,19-dihydro-6-methoxy-17-methyl-6,14-etheno-
morphinan-7-yl]-ethanone (20)
Supporting Information
1H and 13C NMR spectra of key compounds are available in
the Supporting Information.
Acknowledgements
The authors are grateful to the following agencies for finan-
cial support of this work: Noramco, Inc., Natural Sciences
and Engineering Research Council of Canada (NSERC)
(Idea to Innovation and Discovery Grants), Canada Research
Chair Program, Canada Foundation for Innovation (CFI),
Research Corporation, TDC Research, Inc., TDC Research
Foundation, and Brock University.
Oripavine carbonate 19 (50 mg, 0.14 mmol) was suspended
in a 4:1 mixture of distilled water (1.0 mL) and methyl vinyl
ketone (0.25 mL) and the reaction mixture was stirred at
808C for 18 h. The resulting solution was concentrated by
rotary evaporation and the crude mixture was purified by
chromatography on silica gel with dichloromethane/metha-
nol (10:1) as eluent to afford 20 as a colorless oil; yield:
48 mg (81%); [a]2D0: À192.0 (c 0.3, CH2Cl2); Rf =0.61 (10:1;
CH2Cl2/MeOH); IR (film): v=3507, 2934, 2842, 2798, 1765,
1703, 1614, 1491, 1449, 1369, 1356, 1241, 1201, 1168, 1061,
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