Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Article abstract of DOI:10.1039/c3ra43417f

For the use of analytics, European pharmacopoeial impurities A, B, C, and D of cabergoline were synthesized. Ergocryptine was chosen as a starting material and synthesis was accomplished via two approaches, different in length and stereochemical outcome. A longer, indirect approach was realized through otherwise problematic oxidations of the 9,10-dihidrolysergol derivative, to the corresponding aldehyde and carboxylic acid. This was achieved by the use of activated DMSO and a Pinnick oxidation sequence. All four synthesized impurities are used as analytical standards in cabergoline manufacturing processes.

Full text of DOI:10.1039/c3ra43417f

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ARTICLE TYPE
Synthesis of European Pharmacopoeial Impurities A, B, C, and D of
Cabergoline
Jernej Wagger,*a Aljaž Požesb and Franc Požganb.c
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
For the use of analytics, European Pharmacopoeial impurities A, B, C, and D of cabergoline were
synthesized. Ergocryptine was chosen as a starting material and synthesis was accomplished via two
approaches, different in length and stereochemical outcome. Longer, indirect approach was realized
through otherwise problematic oxidations of 9,10ꢀdihidrolysergol derivative, to corresponding aldehyde
10 and carboxylic acid. This was achieved by the use of activated DMSO and Pinnick oxidation sequence.
All four synthesized impurities are used as analytical standards in cabergoline manufacturing process.
O
H
Introduction
N
N
6N
8
9
H
5
Cabergoline (1) is a natural productꢀbased drug, representing a
complex, branched amide of 6ꢀNꢀallylated 9,10ꢀdihydrolysergic
15 acid (cabergolinic acid) A (Figure 1). Primarily acting as a
dopaminergic D2 receptor agonist, cabergoline is most widely
used for treatment of hyperlactonemia disorders and both early
and advanced Parkinson’s disease.1 The structure of cabergoline
also encodes for different biogenic amines than dopamine,
20 therefore displaying modest pharmacodynamic properties
towards adrenergic and serotonergic receptors.1
HN
O
10
H
1
N
H
1
O
O
H
H
H
H
HO
N
N
N
H
N
H
N
H
N
H
O
One of the fundamental roles of the pharmaceutical industry
is to develop new drugs that are safe, effective and of high quality
when they reach the patients. With respect to this, delivering an
25 impurity profile of an active pharmaceutical ingredient (API) is a
must for fulfilling the aforementioned criteria.2 For the purpose of
qualifying and/or quantifying the impurity profile of cabergoline
(1) as the API, we have synthesized four known impurities,
qualified by European Pharmacopoeia (Ph. Eur.)3 as impurities A,
30 B, C and D (Figure 1).
HN
B
A
O
O
H
H
H
H
N
N
N
N
N
H
N
H
N
H
HN
O
N
H
O
HN
C
D
45 Fig. 1 Cabergoline (1) and Ph. Eur. impurities of cabergoline A, B, C and
D.
The genesis of these impurities can be found in the syntheses and
35
other manufacturing process activities of cabergoline (Scheme
1).4
40
50
Scheme 1 Possible routes of cabergoline impurities formation. Some
impurities (A, D) can represent syntheses intermediates or are formed via
hydrolysis of amide bonds from cabergoline (1) or other impurities (B,
C).
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Since cabergoline (1), with the maximum weekly dosage of 40 intermediate 7. This Nꢀdemethylation sequence was already
2.0 mg, falls into low dosing drugs, the threshold for
identification and qualification of impurities in API is usually
0.10% and 0.15% of mass, respectively.2 These limits are low and
efficient production processes should not exceed them. Therefore
reported earlier and slight procedure modifications were used in
our case.8 We have noticed that intermediate 7 decomposes
slowly in acetic acid and is photolabile and therefore, the reaction
yield depends on the swiftness of workꢀup and isolation. 6ꢀNꢀ
5
production syntheses are usually neither suitable nor cost 45 Allylation of 7 was then realized by reaction with allylbromide
effective means to produce impurities for the use of analytics.
Often, new synthesis routes have to be designed to obtain desired
impurities and this was also our task. Synthesis routes for Ph.
and potassium carbonate in dimethylformamide, giving allylated
intermediate 8 in a high yield (Scheme 3).9
10 Eur. impurities A, B, C and D of cabergoline (1) were designed
and results are presented in this paper.
Results and Discussion
9,10ꢀDihydrolysergic acid (2) was selected as one of the key
synthetic intermediates. Although there are several total syntheses
15 of lysergic acid available, through which 9,10ꢀdihydrolysergic
acid (2) could be prepared, αꢀergocryptine (3) was chosen as
starting material. The reason is that αꢀergocryptine (3) is
biosynthetically produced at our production site and way of
preparing 9,10ꢀdihydrolysergic acid (2) from αꢀergocryptine (3) is
20 advantageous over total synthesis because it is shorter, easier and
more economical. Also, there is a longstanding tradition of ergot
alkaloids chemistry within Sandoz company, pioneered by Albert
Hofmann.
Scheme 3 Synthesis of 6ꢀNꢀallylated 9,10ꢀdihydrolysergic acid methyl
50 ester 8.
Starting with αꢀergocryptine (3), the double bond between
25 C9ꢀC10 was diastereoselectively hydrogenated and the reduced
ergopeptine 4 was cleaved by alkaline hydrolysis to give 9,10ꢀ
dihydrolysergic acid (2).5 To increase solubility of 9,10ꢀ
dihydrolysergic acid (2) in organic solvents, the corresponding
methyl ester 5 was prepared (Scheme 2).6
At this point, intermediate 8 served us for the synthesis of
impurities A and D. Alkaline hydrolysis of methyl ester 8 gave
cabergolinic acid, termed as impurity A by Ph. Eur., in 82%
yield. The impurity D was prepared directly from methyl ester 8
55 as well. By reacting 8 with 3ꢀ(dimethylamino)ꢀ1ꢀpropylamine in
acetic acid, direct amidation of ester gave impurity D in 74%
yield (Scheme 4).4
O
O
H
H
H
H
H2N
N
HO
N
O
N
H
H
1M NaOH
MeOH, reflux
AcOH, reflux
(74%)
(82%)
N
H
N
H
8
A
O
H
H
N
N
N
H
H
N
H
D
Scheme 4 Synthesis of Ph. Eur. impurities A and D from intermediate 8.
30
60
Compared to A and D, both impurities B and C have an
ethylcarbamoyl functionality on the indole nitrogen. Since such
functionalization of indole nitrogen requires the use of base,
epimerization at the C8 position of ester 8 was possible. Although
the stereocenter at C8 in 9,10ꢀdihydrolysergic acid (2) is less
Scheme 2 Synthesis of 9,10ꢀdihydrolysergic acid methyl ester 5.
In the next steps allylic substituent on 6ꢀN of 5 had to be
introduced. To introduce the allylic substituent on 6ꢀN of 5, 9,10ꢀ
dihydrolysergic acid (2) had to be Nꢀdemethylated first. 2,2,2ꢀ
65 prone to epimerization under basic conditions than in lysergic
acid, due to the absence of C9ꢀC10 double bond, epimerization
does occur.10,11 For example, it is known from the literature, that
exposing compound 5 to 4 equivalents of NaH in THF at 20 C,
app. 30% of the opposite, thermodynamically les favourable,
35 Trichloroethyl chloroformate (TrocCl) was used, in
a
transformation mechanistically analogues to the von Braun
reaction,7 to Nꢀdemethylate 9,10ꢀdihydrolysergic acid methyl
ester (5). Subsequent zinc mediated reductive cleavage of 6ꢀNꢀ
Troc substituted compound 6 gave the desired 6ꢀNꢀdemethylated
o
2
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axial epimer is observed, and by exposing compound 8 to 4
equivalents of LDA in THF at –20 oC, almost 71 % of axial
epimere is generated.11 Therefore, for installing the
ethylcarbamoyl fragment on the indole nitrogen Nꢀ1 we have
envisioned two different approaches. In the first one, a direct
fucntionalization of Nꢀ1 of 8, under basic conditions with EtNCO
was planned. Being aware of the potential epimerisation
problems under these conditions, a second indirect approach was
envisioned. In this, indirect approach it was planned to reduce C8
5
10 carbonyl group of
8 to corresponding alcohol, do the
functionalization of Nꢀ1 with EtNCO under basic conditions and
then reoxidise the alcohol back to the corresponding carboxylic
acid. Although longer, this reduction/oxidation approach, in
comparison to the first direct one, would ensure us with the
15 epimerisation free preparation of the desired carboxylic acid.
Since both approaches for functionalization of Nꢀ1, direct and
indirect one, have advantages and disadvantages, we have
decided to test both of them. Subjecting methyl ester 8 to the 1.1
equivalents of NaH and EtNCO afforded the desired epimere 9a
20 in 6:1 diastereomeric ratio and with 47 % isolated yield (Scheme
5a).12 With the methyl ester 9a in hand we were only one step
short of the key intermediate 9,10ꢀdihydrolysergic acid 10, which
would enable us to prepare impurities B and C. Luckily
saponification of the methyl ester 9a proceeded selectively with
25 respect to the Nꢀ1 ethylcarbamoyl fragment. This has provided us
with the desired 9,10ꢀdihydrolysergic acid derivative 10 in 77%
yield. We found 9,10ꢀdihydrolysergic acid 10 rather difficult to
isolate, since it displays modest solubility in both organic
solvents and water, but with acid 10 in hand, the door towards
30 completion of the synthesis plan was open (Scheme 5a).
Scheme 5 Synthesis of 13ꢀIntroduction of an ethylcarbamoyl fragment
45 onto the indole nitrogen of lysergol derivative 12.
For the next steps, TBDMSꢀprotected alcohol group in 13 had
to be removed and free alcohol reoxidized back to carboxylic
acid. Deprotection of silyl ether in 13 with TBAF gave 9,10ꢀ
dihydrolysergol derivative 14 in very good yield, although some
50 temperature dependent chemoselectivity was observed. When
silyl deprotection was performed at 0 oC, slow but clean
conversion of 13 to 14 was achieved. On the other hand, when the
reaction was done at room temperature, removal of the
ethylcarbamoyl group was observed in addition to silyl
55 deprotection. 9,10ꢀDihydrolysergol derivative 14 was then used
for subsequent oxidation reaction. Ideally a oneꢀstep oxidation
procedure from primary alcohol 14 to the corresponding
carboxylic acid would be a method of choice. But surprisingly,
while searching the literature, we learned that examples covering
60 oxidations of 9,10ꢀdihydrolysergols and their derivatives to the
corresponding 9,10ꢀdihydrolysergals and/or 9,10ꢀdihydrolysergic
acids are very scarce. In the most recent literature, Křen et al.
reported on their efforts to oxidize Nꢀ1ꢀprotected lysergol
derivatives to aldehydes and acids.14 Beside that, patent literature
65 covers two examples of 9,10ꢀdihydrolysergol oxidations. In the
first one BAIB/TEMPO was used for direct oxidation of 9,10ꢀ
dihydrolysergol derivative to the corresponding 9,10ꢀ
dihydrolysergic acid.15 Unfortunately, BAIB/TEMPO mediated
oxidation did not work in our case, giving only traces of the
70 desired acid, and failure to oxidize the alcohol 14 is in agreement
with the results reported in the literature.14 In the second literature
example, slightly modified ParikhꢀDoering oxidation (SO3ꢁTEA,
DMSO, TEA) was successfully used to oxidize 9,10ꢀdihydroꢀ
lysergol to the 9,10ꢀdihydrolysergal,16 but as reported by Křen,
75 they were unsuccessful in repeating this type of oxidation under
standard ParikhꢀDoering conditions (SO3ꢁPy, DMSO, TEA).14
Since 9,10ꢀdihidrolysergol derivatives are poorly soluble in
various solvents, we anticipated that DMSO mediated oxidations
could be a good choice amongst the plethora of alcohol oxidation
80 methods. DMSO should address the solubility issue of 9,10ꢀ
dihydrolysergol derivative and concurrently serve as an oxidant.
Since contrary reports about effectiveness of the ParikhꢀDoering
oxidation of 9,10ꢀdihidrolysergols were available in the literature,
we have decided to try other analogues reaction. Luckily one can
85 chose among different DMSO mediated oxidations. Indeed, when
Scheme 5 Direct synthesis of the key 9,10ꢀdihydrolysergic acid 10ꢀ
functionalization of the 9,10ꢀdihydrolysergic acid methyl ester 8.
For the indirect approach, methyl ester 8 had to be reduced first.
35 Reacting ester 8 with the LiAlH4 in THF proceeded smoothly and
in high yield to give 9,10ꢀdihydrolysergol derivative 11.13
Hydroxy group in 9,10ꢀdihydrolysergol derivative 11 was
protected as TBDMS ether 12 and a carbamoyl moiety was
introduced by reacting 12 with sodium hydride and
40 ethylisocyanate to give TBDMSꢀprotected 9,10ꢀdihydrolysergol
derivative 13 (Scheme 5).
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alcohol 14 was subjected to PfitznerꢀMoffatt oxidation
isolysergal into the corresponding lysergic acid.20 Indeed, upon
subjecting aldehyde 15 to Pinnick oxidation, the desired 9,10ꢀdiꢀ
hydrolysergic acid 10 was obtained, in 69% yield (Scheme 6).21
9,10ꢀDihydrolysergic acid 10 was then used to synthesize
conditions,
a clean and high yielding conversion to the
corresponding 9,10ꢀdihydrolysergal 15 was observed.17 Here
again temperature dependence on reaction selectivity was
5
observed. Below 5 oC the reaction was clean, giving only 45 both impurities
B and C. The coupling of 10 with 3ꢀ
aldehyde as a product, while at room temperature or higher
several side products could be observed by TLC. Since we were
successful with PfitznerꢀMoffatt oxidation of 14, the question
was raised, whether the outcome of ParikhꢀDoering reaction, on
(dimethylamino)ꢀ1ꢀpropylamine by the use of CDI furnished the
impurity B in 54% yield. For the synthesis of impurity C a more
complex Nꢀacylurea appendage on C8 had to be installed. In the
original synthesis of cabergoline, this side chain was installed
10 the same alcohol substrate would be analogues? Oxidation of the 50 with the use of EDCꢁHCl, by exploiting the usually undesired
alcohol 14, under the ParikhꢀDoering conditions, proceeded
smoothly, affording aldehyde 15 in slightly lower yield than via
PfitznerꢀMoffatt reaction (Scheme 6).18
ability of carbodiimide coupling reagents to form Nꢀacylureas as
intramolecular rearrangement side products.22 Reacting
cabergolinic acid A with EDCꢁHCl, in the absence of an external
nucleophile, Mantegani and coꢀworkers synthesized cabergoline
55 (1).4 Although the use of EDCꢁHCl gives the desired Nꢀacylurea
appendage in one step, a disadvantage of using this asymmetric
carbodiimide is concomitant formation of regioisomeric Nꢀ
acylurea and tedious separation of both isomers.
To compensate for disadvantage of applying EDCꢁHCl,
60 different synthetic strategy was utilized in which excess
ethylisocyanate was reacted with compound D to install Nꢀ
acylurea appendage. Unfortunately the use of ethylisocyanate is
also the root cause for formation of impurities B and C as side
products in cabergoline (1) synthesis (Scheme 1).4 Other methods
65 for Nꢀacylurea installation in cabergoline (1) synthesis were also
developed, although none of them introduces Nꢀacylurea
appendage in one step from the corresponding 9,10ꢀ
dihydrolysergic acid.23 Therefore, compromising lower yield, we
have used EDCꢁHCl in DCM24 for the synthesis of impurity C,
70 thus preparing the desired impurity and its regioisomer 16 in ratio
5:1 respectively.25 After separation of regioisomers, the impurity
C was obtained in 58% yield (Scheme 7).
15
Scheme 7 Indirect, oxidative route to the 9,10ꢀdihydrolysergic acid 10.
An added value of this oxidation transformations also lie in
the 9,10ꢀdihydrolysergal itself. Knowing that aldehydes of this
type are difficult to prepare and that pharmacological activity of
20 synthetically modified ergot alkaloids varies mainly because of
the nature and configuration of substituents on C8, such
aldehydes also represent valuable medicinal chemistry
intermediates.4a,16a,19
Oxidations of 9,10ꢀdihydrolysergals to the corresponding
25 9,10ꢀdihydrolysergic acids are hardly reported in the literature.
This is mainly due to the fact that 9,10ꢀdihydrolysergic acid
derivatives are easily accessible from naturally occurring lysergic
acid. The literature reports on oxidation of 9,10ꢀdihydrolysergal
with Tollens’s reagent or MCPBA, but both methods have their
30 limitations.14 The first one unfortunately gives poor yields while
the second one suffers from chemoselectivity. Peroxy acid
oxidizes not only the aldehyde, but also the nitrogen on position 6
to the corresponding Nꢀoxide. Although reduction of Nꢀoxide to
the desired 9,10ꢀdihydrolysergic acid was demonstrated,14 this
35 method suffers from functional group compatibility, since
allylated lysergal derivatives are not tolerated by peroxy acids nor
catalytic hydrogenation. On the other hand there are some
examples of lysergal oxidations to lysergic acid derivatives. In
the final steps of total synthesis of lysergic acid by Fujii and
40 Ohno, Pinnick oxidation was used to oxidize 1ꢀNꢀ6ꢀNꢀditosylated
Scheme 8 Synthesis of Ph. Eur. impurities B and C.
75
For the synthesis of C, another synthetic strategy would be
viable, by following linear route 10→B→C. By reacting B with
an excess of EtNCO, impurity C could be prepared. In the
original synthesis of cabergoline (1) up to 40 equivalents of
EtNCO were reacted with compound D to get the desired API.
4
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The amount of EtNCO was later reduced in consequent synthesis
50 Experimental
optimizations, by the use of CuI and Ph3P catalysis, to as low as 3
equivalents. Under these, optimised conditions cabergoline (1)
was prepared along with the impurities B and C in the ratio of
82:6:12 respectively.26 As mentioned earlier, other syntheses of
cabergoline (1) were developed to avoid the use of toxic EtNCO
and they are all based on the functionalization of the carboxamide
side chain of D.23 In our case the impurity B was prepared from
precursor 10 in a modest 54% yield. Therefore, if the reaction of
10 B with EtNCO, or any other suitable reagent, would work
quantitatively, the impurity C, starting linearly from 10, would be
prepared in not greater than 54% yield. Following this, we have
never tried to prepare impurity C form 10 via impurity B. Instead,
the impurity C was prepared in one step, directly from carboxylic
15 acid 10 with 58% yield (Scheme 7).
The structure of proper Nꢀacylurea appendage in the impurity
C was determined using 2D COSY NMR technique, where
expected interactions between ethylamido protons were observed
(Figure 2). The proton NMR of the impurity C is also in
20 accordance with the previous report of Mantegani and coꢀ
workers.4
General experimental details
Where stated, anhydrous reactions were carried out in vacuum
oven dried glassware, under stream of nitrogen, passed through
DrieriteTM drying column. Anhydrous solvents were purchased
55 form SigmaꢀAldrich and all reagents were commercial grade,
used without any purification. Exception was αꢀergocryptine
which was acquired through inꢀhouse biofermentation process
and was purified by crystallization from toluene. Reactions were
monitored by thin layer chromatography (TLC) performed on
60 preꢀcoated aluminumꢀbaked silica gel (60 F254, Merck) or
aluminum oxide (60 F254, Merck) plates. Developed TLC plates
were visualized under UV light and/or by aqueous cerium
ammonium molybdate and aqueous potassium permanganate.
Flash chromatography was performed on ZEOPrep 60 Eco 40ꢀ63
65 ꢂm silica gel and aluminum oxide activated, basic, with indicated
mobile phase. Lowerꢀtemperature reactions were performed on
ice/water bath or on MettlerꢀToledo EasyMaxTM synthesis
workstation. Infrared spectra were recorded on a Bruker Alpha
(Platinum ATR) FTꢀIR spectrometer and are reported in
70 reciprocal centimeters (cmꢀ1). Nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker Avance III 500 and
5
1
Bruker Avance DPX 300 spectrometers. Chemical shifts for H
NMR spectra are reported in parts per million from
tetramethylsilane, with the solvent resonance as the internal
75 standard (CDCl3, δ 7.26 ppm, DMSOꢀd6, δ 2.50 ppm). Data are
reported as follows: chemical shift, multiplicity, (s = singlet, d =
dublet, t = triplet, q = quartet, qn = quintet, m = multiplet, br =
broad), coupling constant in Hz and integration. Chemical shifts
for 13C NMR spectra are reported in parts per million from
80 tetramethylsilane, using solvent central peak as the internal
standard (CDCl3, δ 77.16 ppm, DMSOꢀd6, δ 39.52 ppm).Where
stated 2D NMR spectra were recorded. For pH measurements of
water solutions, Seven Easy MettlerꢀToled pH meter was used.
Optical rotations were determined at 589 nm at ambient
85 temperature on PerkinꢀElmer 2400 241MC polarimeter. Data
reported as follows: [α]D, concentration (c in g/100mL) and
solvent. Elemental microanalyses were performed on Perkinꢀ
Elmer Analyser 2400. Mass spectra were obtained using an
AutoSpecQ, QꢀTOF Premier and Agilent 6224 Accurate TOF
90 LC/MS spectrometers. Melting points were determined on a
Kofler micro hot stage and are uncorrected.
Fig. 2 Detected COSY interactions in ethylamido side chain (CH3, 1.18
ppm; CH2, 3.30 ppm; NH, 9.45 ppm) in impurity C are indicated by
25 arrows.
Conclusions
A synthesis of four European pharmacopoeial impurities A, B, C
and D of cabergoline (1) was demonstrated and the synthesized
impurities are used as HPLC analytical standards. To the best of
30 our knowledge, this is the first report on selective synthesis of
these impurities. From αꢀergocryptine (3), 9,10ꢀdihydrolysergic
acid methyl ester (5) was prepared, which served as the key
starting material. Using 5, Nꢀ1 ethylcarbamoyl 9,10ꢀ
dihydrolysergic acid (10) was prepared via two different routes.
35 First route,
a direct one, proceeds through direct Nꢀ1
9,10ꢀDihydroꢀαꢀergocryptine (4) In a 1000 mL roundbottom
flask αꢀergocryptine (3) was weighed (30 g, 52 mmol) and
dissolved in MeOH (500 mL) at 35 C. Then, while stirring, Pd
ethylcarbamoylation of 10, causing partial epimerisation at C8
position. In spite epimerisation, this rout is shorter and therefore
advantageous over the indirect one. Second rout, an indirect one,
follows reductionꢀoxidation of 9,10ꢀdihydrolysergic acid
40 derivative 8, for epimerisation free installation of 1ꢀNꢀ
ethylcarbamoyl moiety. Notwithstanding the fact that oxidations
of 9,10ꢀdihydrolysergol derivatives to the corresponding 9,10ꢀ
dihydrolysergals and further on to 9,10ꢀdihydrolysergic acids are
very rare, we have shown that by combination of activated
45 DMSO and Pinnick reactions this oxidation sequence can be
achieved successfully. Furthermore, such oxidation method of
preparing otherwise scarcely presented 9,10ꢀdihydrolysergals,
can be useful in medicinal chemistry, for preparing novel
pharmacologically active C8ꢀsubstituted derivatives of ergoline.
o
95 (3.9 g, 10% on carbon) suspended in MeOH (143 mL) was added
and reaction mixture was purged with N2. After that reaction
mixture was evacuated, purged with H2 and put under H2
o
atmosphere (balloon). Reaction mixture was stirred at 35 C for
3h and after that it was purged with N2 and heated to 55 oC. At 55
100 oC the Pd catalyst was filtered off and filtrate was ran through
aluminum oxide (30 g, basic) column and column was washed
with MeOH (2x200 mL) heated to 55 oC. Combined MeOH
fractions were evaporated at reduced pressure to dryness and
resuspended in MeOH (450 mL). Suspension was heated to 55 oC
105 and while stirring, H2O (900 mL) was added. Stirred suspension
was cooled to ambient temperature and further to 0 oC, at which it
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was stirred for 0.5 h. Precipitate, was filtered off and dried in
and dried to give titled compound as an off white solid (6.25 g,
vacuum to give the titled compound as an off white solid (28.5 g, 60 85%). Rf : 0.45 (EtOAc : MeOH = 9 : 1); m.p. = 189ꢀ190 oC; [α]D
95%). Optionally, product could be further crystallized from
MeOH. Rf : 0.33 (EtOAc : MeOH = 90% : 10%); m.p. = 224ꢀ226
ꢀ66.1 (c 0.98; DCM); IR: υmax 3142, 3094, 3002, 2947, 2864,
1
2834, 2804, 1729, 1608, 1443, 1238, 1096, 1025, 745 cmꢀ1; H
o
5
oC, lit.5a = 235 C; [α]D ꢀ30.1 (c 0.53; pyr.), lit.5a [α]D ꢀ41 (Pyr.);
NMR (CDCl3, 500 MHz) δ 1.56ꢀ1.66 (m, 1H); 2.21 (ddd, J1 =
11.1 Hz, J2 = 9.4 Hz, J3 = 4.3 Hz, 1H); 2.34ꢀ2,42 (m, 1H); 2.52
IR: υmax 3627, 3369, 3354, 3198, 3064, 2955, 2847, 2792, 1720,
1
1657, 1626, 1546, 1432, 1218, 1191, 1003, 755 cmꢀ1; H NMR 65 (s, 3H); 2.66ꢀ2.75 (m, 1H); 2.94ꢀ3.04 (m, 3H); 3.26ꢀ3.32 (m, 1H);
(DMSOꢀd6, 500 MHz) δ 0.86 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.8
Hz, 3H); 0.94 (d, J = 6.5 Hz, 3H); 1.05 (d, J = 6.7 Hz, 3H); 1.40
3.42 (dd, J1 = 14.7 Hz, J2 = 4.3 Hz, 1H); 3.75 (s, 3H); 6.89 (t, J =
1.6 Hz, 1H); 6.95ꢀ6,98 (m, 1H); 7.16ꢀ7.21 (m, 2H); 8.07 (s, 1H).
13C NMR (CDCl3, 125 MHz) δ 27.0, 30.7, 40.3, 41.6, 43.2, 51.9,
58.8, 66.8, 108.8, 111.9, 113.4, 118.0, 123.3, 126.2, 132.8, 133.5,
10 (q, J = 12.4 Hz, 1H); 1.64ꢀ1.82(m, 3H); 1.85ꢀ2.05 (m, 5H); 2.12
(dt, J1 = 13.5; J2 = 6.7; 1H); 2.22 (t, J = 12.2 Hz, 1H); 2.36 (s,
3H); 2.48ꢀ2.54 (m. 1H); 2.63 (bd, J = 12.2 Hz, 1H); 2.78ꢀ2.84 (m, 70 174.5; HRMS (ESI): m/z calcd. for C17H21N2O2: [M+H]+,
1H); 2.94ꢀ3.02 (m, 2H), 3.30 (dd, J1 = 14.7 Hz, J2 = 4.1 Hz, 1H);
3.35ꢀ3.41 (m, 2H); 3.72 (dd, J1 = 8.4 Hz, J2 = 5.9 Hz, 1H); 4.32
15 (dd, J1 = 7.6 Hz, J2 = 5.8 Hz, 1H); 6.74 (d, J = 7.02 Hz, 1H); 6.98
(bs, 1H); 7.02 (t, J = 7.9 Hz, 1H); 7.13 (d, J = 8.1 Hz; 1H); 7.57
285.1598; found: 285.1595.
9ꢀMethyl 7ꢀ(2,2,2ꢀtrichloroethyl) (6aR,10aR)ꢀ6,6a,8,ꢀ9,10ꢀ
,10aꢀhexahydroindolo[4,3ꢀfg]quinolineꢀ7,9(4H)ꢀdicarboxylate
(6) To an oven dried glassware, dried compound 5 (8.51 g, 29.9
75 mmol) was weighed and anhydrous DCM (200 mL) was added
under N2 atmosphere. Mixture was stirred and TrocCl (18.7 mL,
136 mmol) and DMAP (0.162 g, 1.33 mmol) were added.
Reaction mixture was heated to reflux and stirred for 16 h. After
indicated time reaction mixture was cooled to room temperature,
80 filtered and filtrate was concentrated under reduced pressure.
Residue on evaporation was purified by column chromatography
(EtOAc) to give titled compound as a white solid (10.54 g, 79%).
(d, J = 1.58 Hz, 1H); 9.05 (s, 1H); 10.66 (d, J = 1.55 Hz, 1H). 13
C
NMR (DMSOꢀd6, 125 MHz) δ 15.7, 16.6, 21.5, 22.2, 22.7, 24.3,
26.0, 26.6, 30.5, 33.0, 39.4, 41.8, 42.6, 43.0, 45.7, 52.4, 58.8,
20 63.5, 66.5, 90.15, 103.3, 108.9, 110.0, 111.7, 118.6, 122.1, 125.9,
132.16, 133.20, 164.9, 165.2, 177.1; HRMS (ESI): m/z calcd. for
C32H44N5O5: [M+H]+, 578.3337; found: 578.3337.
(6aR,10aR)ꢀ7ꢀmethylꢀ4,6,6a,7,8,9,10,10aꢀoctahydroindoloꢀ
[4,3ꢀfg]quinolineꢀ9ꢀcarboxylic acid (2) To NaOH (8.28 g, 207
25 mmol) in 250 mL flask, H2O (96 mL) and Na2S2O4 (1.2 g, 6.89
mmol) were added and solution was formed at room temperature.
Rf: 0.89 (EtOAc); m.p. = 211 C, lit.7a 208ꢀ210 C; [α]D ꢀ60.8 (c
0.53; DCM); IR: υmax 3382, 2955, 2847, 1717, 1598, 1436, 1374,
o
o
While stirring, 9,10ꢀdihydroꢀαꢀergocryptine (4) (20 g, 34.6 mmol) 85 1266, 1187, 1146, 1030, 812, 756, 719 cmꢀ1; H NMR (DMSOꢀ
1
was suspended in the solution and reaction mixture was refluxed
for 4h. After that, dark brown solution was cooled to room
30 temperature and acidified with AcOH to pH 6.2. Suspension
d6, 500 MHz) δ 1.67 (m, 1H), 2.74ꢀ2.81 (m, 1H); 3.00ꢀ3.08 (m,
2H); 3.23ꢀ3.33 (m, 2H); 3.63ꢀ3.69 (m, 1H); 3.64 (s, 3H); 3.77
(dd, J1 = 14.2, J2 = 6.2 Hz, 1H); 4.05 (dd, J1 = 14.2, J2 = 2.6 Hz,
1H); 4.84 (d, J = 12.4 Hz, 1H); 4.87 (d, J = 12.4 Hz, 1H); 6.81 (d,
o
formed was cooled bellow 15 C and stirred for 2 h. Suspension
was filtered off, thoroughly washed with H2O and dried to give 90 J = 7.1 Hz, 1H); 7.00 (bs, 1H); 7.03 (m, 1H); 7.17 (d, J = 8.1Hz,
9,10ꢀdihydrolysergic acid (2) as a light grayish solid (8.7 g, 93%).
1H); 10.73 (d, J = 1.5 Hz, 1H). 13C NMR (DMSOꢀd6, 125 MHz)
δ 25.2, 27.1, 36.2, 39.2, 41.8, 51.9, 60.1, 74.1, 96.0, 109.4, 110.2,
112.1, 118.9, 122.0, 125.9, 131.9, 133.4, 153.5, 174.2; HRMS
(ESI): m/z calcd. for C19H20Cl3N2O4: [M+H]+, 445.0483; found:
Rf : 0.58 (THF : AcOH : H2O = 75% : 13% : 12%); m.p. =
o
o
35 decomposition at 250 C, lit.5a compound darkens at 250 C and
decomposes at 300 C; [α]D ꢀ120 (c 0.1; pyr.), lit.5a [α]D ꢀ122 (c
o
0.2; Pyr.); IR: υmax 3370, 3240, 3194, 3117, 3048, 2948, 2852, 95 445.0477.
2348, 1577, 1445, 1390, 1345, 1090, 1029, 1007, 764 cmꢀ1; H
NMR (DMSOꢀd6, 500 MHz) δ 1.34 (q, J = 12.9 Hz, 1H); 2.00
40 (dt, J1 = 10.9 Hz; J2 = 4.1 Hz; 1H); 2.17 (t, J = 11.5 Hz, 1H); 2.37
(s, 3H); 2.48ꢀ2.55 (m, 1H); 2.70ꢀ2.85 (m, 3H); 3.12 (dd, J1 = 11.0
Methyl (6aR,10aR)ꢀ4,6,6a,7,8,9,10,10aꢀoctahydroindoloꢀ
1
[4,3ꢀfg]quinolineꢀ9ꢀcarboxylate (7) Compound 6 (20 g, 44.9
mmol) was suspended in AcOH (885 mL) and MeOH (140 mL)
was added. Suspension was stirred vigorously at room
Hz, J2 = 2.1 Hz, 1H); 3.29 (dd, J1 = 14.6 Hz, J2 = 4.1 Hz, 1H); 100 temperature and Zn (20 g, 306 mmol) was added. After 65 min
6.79 (d, J = 7.1 Hz, 1H); 6.98 (bs, 1H); 7.01 (t, J = 7.6 Hz, 1H);
7.13 (d, J = 8.1 Hz, 1H); 10.65 (s, 1H). 13C NMR (DMSOꢀd6, 125
45 MHz) δ 26.5, 30.5, 40.9, 42.6, 58.6, 66.6, 108.8, 110.0, 112.0,
118.6, 122.1, 125.9, 132.3, 133.2, 175.1; HRMS (ESI): m/z calcd.
for C16H19N2O2: [M+H]+, 271.1441; found: 271.1443.
Zn was filtered off and filtrate was concentrated under reduced
pressure. To the residue on concentration H2O (500 mL) was
added, suspension was stirred for 0.5 h and filtered. Filtrate was
then basified with saturated aqueous NH4OH to pH 8.1, DCM
105 (400 mL) was added and suspension was then acidified with
glacial AcOH back to pH 6.6. Phases were separated and water
phase was again basified with saturated aqueous NH4OH to pH
8.1, DCM (200 mL) was added and pH was adjusted back to pH
6.6 with glacial AcOH. Phases were separated and combined
Methyl (6aR,10aR)ꢀ7ꢀmethylꢀ4,6,6a,7,8,9,10,10aꢀoctahydrꢀ
oindolo[4,3ꢀfg]quinolineꢀ9ꢀcarboxylate
(5)
To
9,10ꢀ
50 dihydrolysergic acid (2) (7.00 g, 25.9 mmol), MeOH (125 mL)
o
was added and suspension was cooled to ~ 3 C. Then slowly,
concentrated H2SO4 (6.7 mL) was added to the suspension. After 110 organic phases were dried over MgSO4, concentrated under
addition of H2SO4, reaction mixture was allowed to warm up to
room temperature and it was stirred for additional 15 h. After that
55 MeOH (58 mL) was partly evaporated, H2O (226 mL) was added
and the solution was basified with 25 % aqueous solution of
reduced pressure to give white solid that was suspended in
heptane (225 mL), stirred for 1 h and filtered. White solid was
washed with heptane and dried to give titled compound (8.6 g,
o
71%). Rf : 0.40 (AcOH : heptane = 1 : 2); m.p. = 173ꢀ175 C,
o
NH4OH to pH 8.80. Suspension formed, was stirred at room 115 lit.27 172 C; [α]D ꢀ24 (c 1.33; DCM); IR: υmax 3402, 3261, 3144,
temperature for 2 h, after which it was filtered, washed with H2O
3093, 3003, 2946, 2861, 2801, 1728, 1601, 1548, 1517, 1435,
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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View Article Online
DOI: 10.1039/C3RA43417F
1
1248, 1234, 1199, 1109, 903, 732 cmꢀ1; H NMR (CDCl3, 500
ide D Compound 8 (0.500 g, 1.6 mmol) was dissolved in 3ꢀ
MHz) δ 1.63ꢀ1.72 (m, 1H); 2.74ꢀ2.92 (m, 6H); 2.96ꢀ3.02 (m, 1H); 60 dimethylaminoꢀ1ꢀpropylamine (3 mL) and glacial acetic acid was
3.05ꢀ3.12 (m, 1H); 3.46ꢀ3ꢀ52 (m, 1H); 3.74 (s, 3H); 6.88 (s, 1H);
6.94 (d, J = 6.7 Hz, 1H); 7.15ꢀ7.22 (m, 2H); 8.03 (bs, 1H). 13C
NMR (CDCl3, 125 MHz) δ 29.6, 30.8, 41.3, 43.0, 48.4, 52.0,
59.6, 109.0, 111.8, 113.3, 117.8, 123.2, 126.6, 132.5, 133.6,
added (0.1 mL) and was stirred for 24 h at reflux temperature.
Then the reaction mixture was cooled to room temperature and
concentrated under reduced pressure to an oily brown residue. To
the residue, EtOAc (100 mL) was added and organic phase was
5
174.4; HRMS (ESI): m/z calcd. for C16H19N2O2: [M+H]+, 65 washed with 10% aqueous NaHCO3 (30 mL) and phases were
271.1441; found: 271.1440.
Methyl (6aR,9R,10aR)ꢀ7ꢀallylꢀ4,6,6a,7,8,9,10,10aꢀoctahyꢀ
10 droindolo[4,3ꢀfg]quinolineꢀ9ꢀcarboxylate (8) Compound
separated. Aqueous phase was reextracted with EtOAc (2x 75
mL) and combined organic phases were washed with brine (2x50
mL). Organic phase was dried over anhydrous MgSO4,
concentrated under reduced pressure and residue was crystallized
7
(8.00 g, 29.6 mmol) was dissolved in DMF (58 mL), while
stirring K2CO3 (8.17 g, 59.2 mmol) and allyl bromide (2.97 mL, 70 from acetone to give titled compound as a light yellowish solid
34.3 mmol) were added. The reaction mixture was stirred at 35
oC for 2.5 h. Then reaction mixture was filtered and EtOAc (350
15 mL) was added. Organic phase was washed with water (4x500
ml) and combined water phases were reextracted with EtOAc
(450 mg, 74%). Rf : 0.18 (EtOAc : EtOH = 88 : 12); m.p. = 201ꢀ
203 oC, lit.4a 200ꢀ202 oC; [α]D ꢀ63.0 (c 0.87; DCM); IR: υmax
3365, 3296, 3067, 2941, 2795, 2719, 1623, 1545, 1443, 1417,
1292, 911, 739 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 1.60ꢀ1.71 (m,
(150 mL). Combined organic phases were dried over Na2SO4, 75 3H); 2.26 (s, 6H), 2.41ꢀ2.45 (m, 2H); 2.48 (t, J = 11.5 Hz, 1H);
concentrated under reduced pressure and dried to give titled
compound as a white solid (8.68 g, 94%). Rf : 0.84 (EtOAc :
2.49ꢀ2.56 (m, 1H); 2.62ꢀ2.68 (m, 1H); 2.68ꢀ2.75 (m. 1H), 2.79ꢀ
2.86 (m, 1H); 2.94ꢀ3.02 (m, 1H); 3.21ꢀ3.26 (m, 1H); 3.36ꢀ3.43
(m, 3H); 3.46 (dd, J1 = 14.5 Hz, J2 = 4.1 Hz, 1H); 3.58 (dd, J1 =
14.4 Hz, J2 = 5.9 Hz, 1H); 5.19 (d, J = 10.1, 1H); 5.25 (dd, J1 =
o
o
20 EtOH = 88 : 12); m.p. = 146ꢀ149 C, lit.10 143ꢀ146 C; [α]D
ꢀ
117.1 (c 1.0; DCM), lit.10 [α]D ꢀ117.2; IR: υmax 3402, 3147, 2948,
1
2838, 1729, 1641, 1610, 1547, 1443, 1365, 1201, 751 cmꢀ1; H 80 17.1 Hz, J2 = 0.8 Hz, 1H); 5.92ꢀ6.03 (m, 1H); 6.87ꢀ6.93 (m, 2H);
NMR (CDCl3, 500 MHz) δ 1.63ꢀ1.73 (m, 1H); 2.49 (t, J = 11.6
Hz; 1H); 2.54 (td, J1 = 10.1 Hz, J2 = 4.8 Hz, 1H); 2.75 (bt, J =
25 13.0 Hz; 1H); 2.90ꢀ3.05 (m, 3H); 3.34 (d, J = 11 Hz, 1H); 3.38ꢀ
3.49 (m, 2H); 3.60 (dd, J1 = 8.6 Hz, J2 = 5.8 Hz, 1H); 3.75 (s,
7.13ꢀ7.20 (m, 2H); 7.64 (bs, 1H); 8.19 (s, 1H). 13C NMR (CDCl3,
125 MHz) δ 25.5, 26.8, 31.1, 40.1, 40.7, 43.8, 45.6, 45.7, 55.8,
56.7, 59.4, 63.7, 108.8, 111.8, 113.2, 118.0, 118.7, 123.2, 126.2,
133.0, 133.4, 133.7, 173.7; HRMS (ESI): m/z calcd. for
3H); 5.23 (d, J = 10.2 Hz, 1H); 5.29 (d, J = 17.1 Hz, 1H); 5.99 85 C23H33N4O: [M+H]+, 381.2649; found: 381.2647.
(m, 1H); 6.89 (s, 1H); 6.95 (d, J = 6.3 Hz, 1H); 7.15ꢀ7.21 (m,
(6aR,9R,10aR)ꢀmethyl 7ꢀallylꢀ4ꢀ(ethylcarbamoyl)ꢀ4,6,6a,7,8,ꢀ
2H); 8.07 (s, 1H) . 13C NMR (CDCl3, 125 MHz) δ 26.7, 30.8,
30 40.5, 41.7, 51.9, 54.8, 56.5, 63.7, 108.8, 111.9, 113.4, 118.0,
118.6, 123.3, 126.2, 132.9, 133.4, 133.8, 174.7; HRMS (ESI): m/z
calcd. for C19H23N2O2: [M+H]+, 311.1754; found: 311.1753.
(6aR,9R,10aR)ꢀ7ꢀAllylꢀ4,6,6a,7,8,9,10,10aꢀoctahydroindoꢀ
lo[4,3ꢀfg]quinolineꢀ9ꢀcarboxylic acid A Compound 8 (0.5 g, 1.6
35 mmol) was dissolved in MeOH ( 15 mL) and aqueous 1M NaOH
solution (4 mL) was added. Reaction mixture was refluxed for 45
min. The reaction mixture was concentrated under reduced
pressure and residue was dissolved in H2O (10 mL). Water
solution was then acidified with AcOH to pH 5.2 and precipitate
40 was stirred at ~ 3 oC (ice/water bath) for 3 h. Precipitate was then
filtered off and washed with water to give impurity A as a white
solid (0.388 g, 82%). Rf : 0.58 (THF : H2O: AcOH = 98 : 1 : 1);
9,10,10aꢀoctahydroindolo[4,3ꢀfg]quinolineꢀ9ꢀcarboxylate (9a)
Compound 8 (0.6 g, 1.90 mmol) in an oven dried roundbottom
flask was dissolved in anhydrous THF (16 mL) under N2
90 atmosphere and cooled to ~ 3 oC (ice/water bath). To the solution
NaH (83.6 mg, 60% in mineral oil, 2.1 mmol,) was added.
Mixture was stirred for additional 10 min and and EtNCO (0.225
mL, 2.8 mmol) was added. Reaction mixture was warmed to
room temperature and stirred for 3 h. After 3 h reaction mixture
95 was cooled to ~ 3 oC and quenched with brine (1 mL).
Suspension was concentrated under reduced pressure and residue
was suspended in DCM (100 mL). Water (75 mL) was added and
phases were separated. Water phase was reextracted with ethyl
acetate (40 mL) and combined organic phases were dried over
100 MgSO4 and concentrated in vacuum.12 Residue on evaporation
was purified using column chromatography to give title
compound as a white solid (0.341 g, 47%). Rf : 0.18 (ethyl acetate
: heptane = 1 : 1); m.p. = 176ꢀ178 oC; [α]D ꢀ126.2 (c 0.16;
DMF.); IR: υmax 3316, 3068, 3021, 2977, 2948, 2858, 2789, 1731,
105 1666, 1604, 1537, 1436, 1341, 1274, 1160, 1116, 1073, 929, 752,
o
m.p. = 246ꢀ247 C; [α]D ꢀ138.4 (c 0.72; DMSO); IR: υmax 3208,
2942, 2322, 1650, 1589, 1448, 1365, 1337, 1283, 952, 757 cmꢀ1;
45 1H NMR (DMSOꢀd6, 500 MHz) δ 1.31ꢀ1.41 (m, 1H); 2.30 (t, J =
11.5 Hz, 1H); 2.29ꢀ2.37 (m, 1H); 2.56 (bt, J = 12.8 Hz, 1H);
2.66ꢀ2.75 (m, 1H); 2.78ꢀ2.86 (m, 2H); 3.16ꢀ3.21 (m, 1H); 3.27
(dd, J1 = 14.6 Hz, J2 = 7.4 Hz, 1H); 3.36 (dd, J1 = 14.6 Hz, J2 =
3.9 Hz, 1H); 3.51 (dd, J1 14.6 Hz, J2 = 5.5 Hz, 1H); 5.17 (d, J =
50 10.2 Hz, 1H); 5.26 (d, J = 17.0 Hz, 1H); 5.90ꢀ6.00 (m, 1H); 6.79
(d, J = 7.1 Hz, 1H); 6.98 (s, 1H); 7.02 (t, J = 7.6 Hz, 1H); 7.14 (d,
J = 8.1 Hz, 1H); 10.65 (s, 1H). 13C NMR (DMSOꢀd6, 125 MHz) δ
26.2, 30.6, 39.9, 40.9, 54.7, 55.6, 63.5, 108.8, 110.1, 112.1,
117.9, 118.6, 122.1, 125.9, 132.4, 133.2, 134.7, 175.2; HRMS
55 (ESI): m/z calcd. for C18H21N2O2: [M+H]+, 297.1598; found:
297.1595.
1
635 cmꢀ1; H NMR (DMSOꢀd6, 500 MHz) δ 1.15 (t, J = 7.2 Hz,
1H); 1.32ꢀ1.42 (m, 1H); 2.28ꢀ2.36 (m, 2H); 2.48ꢀ2.56 (m, 1H);
2.77ꢀ2.86 (m, 3H); 3.15ꢀ3.21 (m, 1H); 3.24ꢀ3.30 (m, 3H); 3.31ꢀ
3.36 (m, 1H); 3.48ꢀ3.55 (m, 1H); 3.65 s, 3H); 5.18 (d, J = 10.3
110 Hz, 1H); 5.27 (d, J = 17.0 Hz, 1H); 5.87ꢀ6.00 (m, 1H); 7.00 (d, J
= 7.4 Hz, 1H); 7.19 (t, J = 7.7 Hz, 1H); 7.52 (d, J = 1.3 Hz, 1H);
7.78 (d, J = 8.2 Hz, 1H); 7.99 (t, J = 5.4 Hz, 1H). 13C NMR
(DMSOꢀd6, 125 MHz) δ 15.0, 25.7, 30.3, 34.9, 40.6, 51.6, 54.3,
55.4, 62.8, 112.9, 115.1, 115.9, 117.9, 118.1, 124.7, 127.1, 132.8,
115 133.1, 134.6, 151.8, 173.7; HRMS (ESI): m/z calcd. for
C22H28N3O3: [M+H]+: 382.2125; 382.2118.
(6aR,9R,10aR)ꢀ7ꢀAllylꢀ4ꢀ(ethylcarbamoyl)ꢀ4,6,6a,7,8,9,10,ꢀ
10aꢀoctahydroindolo[4,3ꢀfg]quinoloneꢀ9ꢀcarboxylic acid (10)
(6aR,9R,10aR)ꢀ7ꢀAllylꢀNꢀ[3ꢀ(dimethylamino)propyl]ꢀ4,6,ꢀ
6a,7,8,9,10,10aꢀoctahydroindolo[4,3ꢀfg]quinolineꢀ9ꢀcarboxamꢀ
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

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Page 8 of 12
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DOI: 10.1039/C3RA43417F
a) via saponification of 9a: In a round bottom flask compound
3.36ꢀ3.43 (m, 3H); 3.49 (dd, J1 = 14.6 Hz, J2 = 5.6 Hz, 1H); 4.54
9a (100 mg, 0.272 mmol) was dissolved in THF:H2O mixture 60 (t, J = 5.3 Hz, 1H); 5.15 (d, J = 10.4 Hz, 1H); 5.24 (d, J = 16.8
(2:1, 6 mL). To the mixture aqueous solution of NaOH (1.0 M,
0.6 mL) was added and reaction mixture was stirred for 1 h. After
that aqueous HCl (1.0 M, 0.9 mL) was added reaction mixture
was concentrated under reduced pressure. The residue on
Hz, 1H); 5.95 (m, 1H); 6.77 (d, J = 7.1 Hz, 1H); 6.96 (bs, 1H);
7.00 (t, J = 7.6 Hz, 1H); 7.11 (d, J = 8.1 Hz, 1H); 10.60 (s, 1H).
13C NMR (DMSOꢀd6, 125 MHz) δ 26.4, 30.9, 38.3, 40.5, 56.1,
56.7, 64.1, 64.6, 108.6, 110.3, 112.0, 117.4, 118.4, 122.0, 126.0,
5
evaporation was purified by column chromatography (THF : H2O 65 133.1, 135.1; HRMS (ESI): m/z calcd. for C18H23N2O: [M+H]+,
: AcOH = 98 : 1: 1) to give titled compound as a yellowish solid
(76.9 mg, 77%).
283.1805; found: 283.1802.
(6aR,9R,10aR)ꢀ7ꢀAllylꢀ9ꢀ[(tertꢀbutyldimethylsilyl)oxy]ꢀ
methylꢀ4,6,6a,7,8,9,10,10aꢀoctahydroindolo[4,3ꢀfg]quinoline
(12) To alcohol 11 (6.00 g, 21.2 mmol) in DMF (150 mL),
10 b) via Pinnic oxidation of 15: To aldehyde 15 (1.84 g, 5.20
mmol), tꢀBuOH (18 mL) and THF (18 mL) were added and
solution was stirred and cooled to ~ 3 oC (ice/water bath). Then 2ꢀ 70 imidazole (4.34 g, 63.8 mmol) and TBDMSꢀCl (4.80 g, 31.9
methylꢀ2ꢀbutene (2.83 mL, 26.86 mmol) was added. To this a
solution of NaH2PO4 (1.89 g, 15.7 mmol) and NaClO2 (1.42g,
15 12.6 mmol, 80%) in H2O (18 mL) was added slowly. Reaction
mixture was stirred for 1.5 h at ~ 3 oC (ice/water bath) and then it
mmol) were added. Reaction mixture was stirred for 2 h at room
temperature after which it was quenched with saturated, aqueous
solution of NaHCO3 (150 mL). To a white suspension, H2O (500
mL) and EtOAc (400 mL) were added and phases were separated
was stopped with addition of Na2SO3 (2.02 g, 16.0 mmol). 75 after addition of brine (30 mL). Water phase was washed with
Precipitate formed was filtered off and filtrate was concentrated
under reduced pressure. Residue on concentration was purified by
20 column chromatography with two different mobile phases used
sequentially. First mobile phase (DCM : MeOH = 10 : 1) was
EtOAc (2x300 mL). Combined organic phases were reextracted
with water (3x400 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Residue was dried at 40 C
o
for 19 h to give titled compound as white solid (8.39 g, 99%). Rf :
used to separate yellow impurities and second mobile phase (THF 80 0.57 (EtOAc : EtOH = 88 : 12); m.p. = 225ꢀ227 oC (from
: H2O : AcOH = 98 : 1: 1) was used to elute product which upon
evaporation and drying gave light yellowish solid (1.33 g, 68%).
25 Rf : 0.57 (THF : H2O : AcOH = 98 : 1: 1); m.p. = 155ꢀ158 C
MeOH); [α]D ꢀ69.0 (c 1.19; DCM); Calc. for: C24H36N2OSi: C,
72.67; H, 9.15; N, 7.06. Found: C, 72.73; H, 9.39; N, 7.10%; IR:
υmax 3096, 3013, 2949, 2929, 2899, 2856, 2813, 2784, 1738,
o
(from EtOAc); [α]D ꢀ73.3 (c 1.19; DMSO); Calc. for:
1645, 1618, 1549, 1518, 1462, 1357, 1217, 1098, 834, 772, 742
1
C21H25N3O3ꢁH2O: C, 65.44; H, 7.06; N, 10.90. Found: C, 65.03; 85 cmꢀ1; H NMR (CDCl3, 500 MHz) δ 0.08 (s, 3H); 0.09 (s, 3H);
H, 6.72; N, 10.58%; IR: υmax 3308, 2962, 2930, 2872, 2854,
0.93 (s, 9H); 1.09ꢀ1.18 (m, 1H); 2.02ꢀ2.16 (m, 2H); 2.49 (dt, J1 =
3.8 Hz, J2 = 10.9 Hz, 1H); 2.66 (d, J = 13.0 Hz, 1H); 2.75 (t, J =
12.7 Hz, 1H); 3.00 (bt, J = 9.1 Hz, 1H); 3.21 ( d, J = 9.5 Hz, 1H);
3.38 (dd, J1 = 14.2 Hz, J2 = 7.5 Hz, 1H); 3.47 (dd, J1 = 14.6 Hz,
1
1677, 1586, 1532, 1439, 1390, 1274, 1035, 753 cmꢀ1. H NMR
30 (DMSOꢀd6, 500 MHz) δ 1.15 (t, J = 7.1 Hz, 3H); 1.27ꢀ1.38 (m,
1H); 2.25ꢀ2.37 (m, 2H); 2.68 (t, J = 10.8 Hz, 1H); 2.76ꢀ2.85 (m,
2H); 3.17 (d, J = 11.1 Hz, 1H); 3.20ꢀ3.48 (m, 5H); 3.52 (dd, J1 = 90 J2 = 3.9 Hz, 1H); 3.51ꢀ3.56 (m, 1H); 3.58ꢀ3ꢀ63 (m, 2H); 5.20 (d,
14.6 Hz, J2 = 3.3 Hz; 1H); 5.17 (d, J = 10.1 Hz, 1H); 5.27 (d, J =
16.9 Hz, 1H); 5.90ꢀ6.00 (m, 1H); 7.01 (d, J = 7.2 Hz, 1H); 7.19
35 (t, J = 7.7 Hz, 1H); 7.52 (s, 1H); 7.87 (d, J = 8.0 Hz, 1H); 7.99
(bs, 1H), 12.50 (bs, 1H). 13C NMR (DMSOꢀd6, 125 MHz) δ 15.0,
J = 10.1 Hz, 1H); 5.26 (d, J = 17.0 Hz, 1H); 5.95ꢀ6.06 (m, 1H);
6.89 (s, 1H); 6.92ꢀ6.95 (m, 1H); 7.15ꢀ7.20 (m, 2H), 8.01 (s, 1H).
13C NMR (CDCl3, 125 MHz) δ ꢀ5.2, ꢀ5.1, 1.2, 18.5, 26.1, 26.8,
29.8, 31.0, 38.7, 40.9, 56.8, 56.9, 64.3, 66.7, 108.58, 112.3,
25.7, 30.5, 34.9, 39.8, 40.8, 54.6, 55.5, 62.9, 112.9, 115.2, 115.9, 95 113.3, 117.8, 118.2, 123.2, 126.4, 133.4, 134.0, 134.1; HRMS
117.8, 118.1, 124.7, 127.2, 133.0, 133.1, 134.7, 151.9, 175.1;
HRMS (ESI): m/z calcd. for C21H26N3O3: [M+H]+, 368.1969;
40 found: 368.1967.
(ESI): m/z calcd. for C24H37N2OSi: [M+H]+, 397.2675; found:
397.2673.
(6aR,9R,10aR)ꢀ7ꢀAllylꢀ9ꢀ[(tertꢀbutyldimethylsilyl)oxy]ꢀ
methylꢀNꢀethylꢀ6a,7,8,9,10,10aꢀhexahydroindolo[4,3ꢀfg]quiꢀ
[(6aR,9R,10aR)ꢀ7ꢀAllylꢀ4,6,6a,7,8,9,10,10aꢀoctahydroindꢀ
olo[4,3ꢀfg]quinolineꢀ9ꢀyl]methanol (11) In a dry roundbottom 100 nolineꢀ4(6H)ꢀcarboxamide (13) Compound 12 (16.00 g, 40.4
flask with compound 8 (0.200 g, 0.64 mmol), anhydrous THF (20
mL) was added under inert atmosphere. The solution was cooled
45 to ~ 3 oC (ice/water bath) and with vigorous stirring LiAlH4 (0.97
mL, 0.97 mmol, 1M/Et2O) was added dropwise. Reaction was
mmol) in an oven dried glassware was dissolved in anhydrous
THF (400 mL) under N2 atmosphere. Solution was cooled to ~ 3
oC (ice/water bath) and NaH (1.86 g, 60% in mineral oil, 44.4
mmol,) was added. Suspension was stirred for additional 10 min
stopped after 45 min with addition of H2O (0.1 mL) and was 105 at indicated temperature and EtNCO (4.80 mL, 60.6 mmol) was
stirred for additional 20 min at indicated temperature. Suspension
was then filtered through celite and washed with EtOAc (2x5
50 mL). Filtrate was concentrated under reduced pressure and dried
added. Reaction mixture was then warmed to room temperature
and stirred for 3 h. After 3 h reaction mixture was cooled to ~ 3
oC and quenched with brine (20.4 mL). Suspension was
concentrated under reduced pressure, oily residue was dissolved
in vacuum to give titled compound as white solid (157.5 mg,
o
87%). Rf : 0.25 (EtOAc : EtOH = 88 : 12); m.p. = 206ꢀ209 C, 110 in DCM (1000 mL) and washed with H2O (400 mL). Water phase
lit.8 204ꢀ206 oC; [α]D ꢀ74.4 (c 0.91, DMSO); IR: υmax 3240, 3056,
was then reextracted with DCM (2x250 mL) and, combined
organic phases were additionally washed with water (200 mL).
Organic phase was dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give brown solid, which
2923, 2847, 1868, 1797, 1644, 1612, 1552, 1469, 1445, 1342,
1
55 1035, 733 cmꢀ1; H NMR (DMSOꢀd6, 500 MHz) δ 0.88ꢀ0.97 (m,
1H); 1.94 (t, J = 10.9 Hz, 1H); 2.27 (td, J1 = 10.2 Hz, J2 = 4.1 Hz,
1H); 2.52ꢀ2.59 (m, 2H); 2.73ꢀ2.80 (m, 1H); 3.07 (d, J = 9.9 Hz, 115 was purified by column chromatography (EtOAc : heptane = 1 :
1H); 3.23 (dd, J1 = 14.6 Hz, J2 = 7.6 Hz, 1H); 3.26ꢀ3.31 (m, 1H);
3) to give titled compound as pale yellow solid (16.94 g, 90%). Rf
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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DOI: 10.1039/C3RA43417F
: 0.38 (EtOAc : heptane = 1 : 3); m.p. = 135ꢀ137 oC (from
MeOH/H2O); [α]D ꢀ75.9 (c 1.40; DCM); Calc. for: C27H41N3O2Si: 60 8.49 mmol) was dissolved in anhydrous DMSO (20 mL) and
a) via PfitznerꢀMoffatt oxidation of 14: Alcohol 14 (3.00 g,
C, 69.33; H, 8.84; N, 8.98. Found: C, 69.58; H, 9.11; N, 9.02%;
IR: υmax 3377, 2952, 2925, 2853, 2810, 1737, 1661, 1605, 1535,
1460, 1449, 1438, 1291,1087, 837, 780, 754 cmꢀ1; 1H NMR
(CDCl3, 500 MHz) δ 0.07 (s, 3H); 0.08 (s, 3H); 0.91 (s, 9H);
anhydrous DCM (20 mL) under N2 atmosphere. Solution was
cooled to ~ 3 C (ice/water bath) and with stirring DCC (5.26 g,
o
5
25.5 mmol), anhydrous pyridine (1.38 mL, 17 mmol) and TFA
(0.99 mL, 12.7 mmol) were added sequentially. Reaction mixture
1.05ꢀ1.13 (m, 1H); 1.28 (t, J = 7.2 Hz, 3H); 2.00ꢀ2.13 (m, 2H), 65 was stirred for 1.5 h at ~ 3 oC (ice/water bath). Suspension
2.40 (td, J1 = 11.2 Hz, J2 = 3.9 Hz, 1H); 2.58ꢀ2.63 (m, 2H); 2.91
(bt, J = 9.1 Hz, 1H); 3.18 (d, J = 8.6 Hz, 1H); 3.31 (dd, J1 = 14.5
10 Hz, J2 = 7.6 Hz, 1H); 3.36 (dd, J1 = 15.0 Hz, J2 = 3.9 Hz, 1H);
3.46ꢀ3.64 (m, 5H); 5.19 (d, J = 10.2 Hz, 1H); 5,24 (d, J = 17.1
formed was filtered and to the filtrate DCM (250 mL) was added
and organic phase was washed with water (3x250 mL).
Combined water phases were reextracted with DCM (250 mL).
Then combined organic phases were dried over anhydrous
Hz, 1H); 5.66 (bs, 1H); 5.90ꢀ6.01 (m, 1H); 7.04 (d, J = 7.3 Hz, 70 Na2SO4, concentrated under reduced pressure and residue was
1H); 7.20 (s, 1H); 7.27 (t, J = 7.8 Hz, 1H); 7.72 (d, J = 8.2 Hz,
1H). 13C NMR (CDCl3, 125 MHz) δ ꢀ5.23, ꢀ5.19, 15.1, 15.3, 18.4,
15 26.1, 26.5, 29.8, 30.9, 35.9, 38.5, 40.5, 56.6, 56.7, 63.8, 66.6,
111.7, 116.4, 116.5, 117.9, 118.4, 125.3, 128.4, 132.8, 133.8,
purified by column chromatography (MeOH : EtOAc = 10 : 90
and DCM : MeOH = 90 : 10) to give titled aldehyde as a white
solid (2.60 g, 87%).
b) via ParikhꢀDoering oxidation of 14: In an oven dried, round
134.4, 152.5; HRMS (ESI): m/z calcd. for C27H42N3O2Si: 75 bottom flask, alcohol 14 (50 mg, 0.141 mmol) under N2
[M+H]+, 468.3041; found: 468.3040.
atmosphere, was dissolved in anhydrous DMSO (2 mL) and to
the solution anhydrous DCM (2 mL) was added. Et3N (0.197 mL,
1.41 mmol) was added and reaction mixture was cooled to ~ 3 oC
(ice /water bath). To this solution SO3ꢁPy (67.4 mg, 0.423 mmol)
(6aR,9R,10aR)ꢀ7ꢀAllylꢀNꢀethylꢀ9ꢀ(hydroxymethyl)ꢀ6a,7,8,ꢀ
20 9,10,10aꢀhexahydroindolo[4,3ꢀfg]quinolineꢀ4(6H)ꢀcarboxamꢀ
ide (14) Compound 13 (4.5 g, 9.6 mmol) was dissolved in THF
(50 mL). Solution was cooled to 0 oC, TBAF (19.2 mL, 19.2 80 dissolved in anhydrous DMSO (0.25 mL) was added dropwise
mmol, 1M in THF) was added and reaction mixture was stirred at
indicated temperature for 45 h. After that H2O (0.38 mL) was
25 added and reaction mixture was concentrated under reduced
pressure. Residue was purified by column chromatography
and reaction mixture was stirred for 80 min. After that time
reaction mixture was poured in to H2O (20 mL) and water phase
was extracted with DCM (3x15 mL). Combined organic phases
were dried over MgSO4 and concentrated under reduced pressure.
(EtOH : EtOAc = 12 : 88), to give titled compound as a white 85 Residue on concentration was purified by column
solid (3.21 g, 94%). Rf : 0.38 (EtOH : EtOAc = 12 : 88); m.p. =
190ꢀ193 oC (from toluene); [α]D ꢀ92.5 (c 1.26; DMSO); Calc. for:
30 C21H27N3O2: C, 71.36; H, 7.70; N, 11.89. Found: C, 71.65; H,
8.02; N, 11.89%; IR: υmax 3424, 3303, 2932, 2913, 2856, 2812,
chromatography (EtOH : EtOAc = 1 : 9) to give aldehyde 15 as a
white solid (33.7 mg, 68%). Rf : 0.56 (MeOH : EtOAc = 10 : 90);
m.p. = 165ꢀ167 oC (from DCM/heptane); [α]D ꢀ70.0 (c 0.45;
DCM); Calc. for: C21H25N3O2: C, 71.77; H, 7.17; N, 11.96.
2784, 1664, 1603, 1533, 1439, 1243, 1142, 1039, 918, 812, 748 90 Found: C, 71.61; H, 7.31; N, 11.84 %; IR: υmax 3320, 2927, 2849,
cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 1.08ꢀ1.18 (m, 1H); 1.30 (t, J
= 7.2 Hz, 3H); 1.80 (bs, 1H); 2.08ꢀ2.17 (m, 2H); 2.44 (td, J1 =
35 10.5 Hz, J2 = 4.0 Hz, 1H); 2.63ꢀ2.71 (m, 2H); 2.92ꢀ2.93 (m, 1H);
3.16ꢀ3.24 (m, 1H); 3.34ꢀ3.43 (m, 2H); 3.49ꢀ3.55 (m, 2H); 3.55ꢀ
1726, 1668, 1623, 1566, 1535, 1437, 1242, 1085, 892, 752, 640
1
cmꢀ1; H NMR (CDCl3, 300 MHz) δ 1.30 (t, J = 7.2 Hz, 3H);
1.35ꢀ1.45 (m, 1H); 2.31 (t, J = 11.6 Hz, 1H); 2.42ꢀ2.50 (m, 1H);
2.65ꢀ2.75 (m, 1H); 2.85ꢀ3.05 (m, 3H); 3.30ꢀ3.44 (m, 3H); 3.45ꢀ
3.62 (m, 2H); 3.66 (dd, J1 = 10.8 Hz, J2 = 4.7 Hz, 1H); 5.21 (d, J 95 3.63 (m, 3H); 5.19ꢀ5.32 (m, 2H); 5.59 (bt, J = 5.0 Hz, 1H); 5.90ꢀ
= 10.2 Hz, 1H); 5.26 (d, J = 16.8 Hz, 1H); 5.50 (t, J = 4.7 Hz,
1H); 5.92ꢀ6.02 (m, 1H); 7.06 (d, J = 7.4 Hz, 1H); 7.20 (d, J = 1.3
40 Hz, 1H); 7.28 (t, J = 8.0 Hz, 1H); 7.69 (d, J = 8.2 Hz, 1H); H
6.00 (m, 1H); 7.07 (d, J = 7.4 Hz, 1H); 7.21 (d, J = 1.6 Hz, 1H);
7.30 (t, J = 7.6 Hz, 1H); 7.72 (d, J = 8.3 Hz, 1H); 9.76 (s, 1H).
13C NMR (CDCl3, 75.5 MHz) δ 15.3, 26.4, 27.9, 36.0, 40.2, 48.6,
52.5, 56.5, 63.5, 112.0, 115.9, 116.5, 118.2, 118.9, 125.4, 128.3,
1
NMR (DMSOꢀd6, 500 MHz) δ 0.85ꢀ0.95 (m, 1H); 1.15 (t, J = 7.2
Hz, 3H); 1.95 (dd, J1 = 22.3 Hz, J2 = 11.2 Hz; 1H); 2.25 (dt, J1 = 100 132.8, 133.3, 133.4, 152.4, 202.6; HRMS (ESI): m/z calcd. for
10.3 Hz, J2 = 3.8 Hz; 1H); 2.46ꢀ2.53 (m, 1H), 2.56 (bd, J = 12.7
Hz, 1H); 2.71ꢀ2.79 (m, 1H); 3.07 (d, J = 10.2 Hz, 1H); 3.22 (dd,
45 J1 = 14.6 Hz, J2 = 7.7 Hz; 1H); 3.25ꢀ3.32 (m, 3H); 3.32ꢀ3.42 (m,
3H); 3.50 (dd, J1 = 14.6 Hz, J2 = 5.3 Hz; 1H); 4.57 (t, J = 5.1 Hz,
C21H26N3O2: [M+H]+, 352.2020; found: 352.2019.
(6aR,9R,10aR)ꢀ7ꢀAllylꢀN9ꢀ[3ꢀ(dimethylamino)propyl)ꢀN4ꢀ
ethylꢀ6a,7,8,9,10,10aꢀhexahydroindolo[4,3ꢀfg]quinolineꢀ4,9ꢀ
(6H)ꢀdicarboxamide B Carboxylic acid 10 (0.580 g, 1.58 mmol)
1H); 5.16 (d, J = 10.3 Hz, 1H); 5.24 (d, J = 17.1 Hz, 1H); 5.89ꢀ 105 in oven dried glassware was dissolved in anhydrous DMF (10
5.99 (m, 1H); 6.98 (d, J = 7.3 Hz, 1H); 7.18 (t, J = 7.8 Hz, 1H);
7.50 (s, 1H); 7.85 (d, J = 8.2 Hz, 1H); 7.97 (t, J = 5,4 Hz, 1H).
50 13C NMR (CDCl3, 125 MHz) δ 15.3, 26.5, 30.9, 36.0, 38.6, 40.5,
56.4, 56.8, 63.7, 66.5, 111.7, 116.3, 116.6, 118.4, 118.8, 125.4,
mL) under N2 atmosphere and CDI (0.267 g, 1.74 mmol) was
added. Mixture was stirred at room temperature for 3.5 h and then
3ꢀdimethylaminoꢀ1ꢀpropylamine (0.221 mL, 1.74 mmol) was
added. Reaction mixture was stirred at room temperature for 20 h.
128.4, 132.7, 133.5, 134.2, 152.4; 13C NMR (DMSOꢀd6, 125 110 After indicated time, H2O (100 mL) was added and reaction
MHz) δ 15.0, 25.9, 30.8, 34.9, 38.2, 40.1, 56.1, 56.5, 63.6, 64.6,
112.7, 115.4, 115.9, 117.6, 118.0, 124.7, 127.3, 133.1, 133.6,
55 134.9, 151.9; HRMS (ESI): m/z calcd. for C21H28N3O2: [M+H]+,
354.2176; found: 354.2177.
(6aR,9R,10aR)ꢀ7ꢀAllylꢀNꢀethylꢀ9ꢀformylꢀ6a,7,8,9,10,10aꢀ
hexahydroindolo[4,3ꢀfg]quinolineꢀ4(6H)ꢀcarboxamide (15)17,18
mixture was extracted with DCM (4x75 mL). Combined organic
fractions were washed with H2O (3x100 mL) and concentrated
under reduced pressure. Residue on evaporation was suspended
in H2O (75 mL). Suspension was cooled to ~ 3 oC (ice/water
115 bath) and acidified with 1M aqueous HCl to pH 3.75 to obtain
solution which was filtered and extracted with DCM (2x75 mL).
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

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DOI: 10.1039/C3RA43417F
Organic phases were discarded and water phase was reꢀcooled to
~ 3 C (ice/water bath), basified with 1M aqueous NaOH to pH
Continuing elution, regioisomer 16 was isolated and
evaporation of mobile phase gave (67 mg, 10%) yellow oil. Rf :
o
9.60 and precipitate formed was filtered off and washed with H2O 60 0.29 (pyr. : Me2CO = 10 : 90); [α]D ꢀ40.2 (c 0.10; DCM); IR: υmax
(20 mL). Solid residue on filtration was dried to give titled
compound as a pale yellowish solid (0.385 g, 54%). Rf : 0.25
(EtOAc : BuOH : pyr. : DMF = 40 : 25: 10 : 25); m.p. = 205ꢀ207
oC; [α]D ꢀ75.4 (c 0.83; DCM); IR: υmax 3294, 3066, 2934, 2861,
3282, 2971, 2935, 2868, 2817, 2785, 2246, 1688, 1524, 1438,
1
5
1340, 1271, 1139, 917, 729 cmꢀ1; H NMR (CDCl3, 500 MHz) δ
1.28 (t, J = 7.2 Hz, 3H); 1.30 (t, J = 6.7 Hz, 3H); 1.72ꢀ1.83 (m,
3H); 2.27 (s, 6H); 2.40 (m, 2H); 2.50ꢀ2.66 (m, 3H); 2.74 (d, J =
2765, 2725, 1663, 1639, 1535, 1439, 1346, 1212, 919, 751 cmꢀ1; 65 13.0 Hz, 1H); 2.92ꢀ2.99 (m, 1H); 3.15 (d, J = 13.4 Hz, 1H); 3.21
1H NMR (CDCl3, 500 MHz) δ 1.28, (t, J = 7.2 Hz, 3H); 1.57 (m,
10 1H); 1.64ꢀ1.71 (m ,2H); 2.26 (s, 6H); 2.35ꢀ2,46 (m, 4H); 2.51ꢀ
2.58 (m, 1H); 2.58ꢀ2.64 (m, 1H); 2.72ꢀ2.78 (m, 1H); 2.79ꢀ2.86
(m, 1H); 3.15ꢀ3.20 (m, 1H); 3.27 (dd, J1 = 14.4 Hz, J2 = 7.7 Hz;
(d, J = 11.4 Hz, 1H); 3.29ꢀ3.36 (m, 3H); 3.39 (dd, J1 = 14.7 Hz, J2
= 3.7 Hz, 1H); 3.47ꢀ3.53 (m, 2H); 3.56 (dd, J1 = 15.2 Hz, J2 = 6.4
Hz, 1H); 3.92 (q, J = 7.0 Hz, 2H); 5.21 (d, J = 10.1 Hz, 1H); 5.26
(d, J = 17.0 Hz, 1H); 5.64 (bt, J = 5.4 Hz, 1H); 5.88ꢀ5.98 (m,
1H); 3.33 (dd, J1 = 14.9 Hz, J2 = 4.0 Hz; 1H); 3.36ꢀ3.40 (m, 2H); 70 1H); 7.02 (d, J = 7.3 Hz, 1H); 7.23 (bs, 1H); 7.27 (t, J = 7.8 Hz,
3.46ꢀ3.54 (m, 3H); 5.17 (d, J = 10.2 Hz, 1H); 5.22 (d, J = 17.1
15 Hz, 1H); 5.79 (t, J = 5.4 Hz, 1H); 5.86ꢀ5.96 (m, 1H); 7.00 (d, J =
7.3 Hz, 1H); 7.22 (bs, 1H); 7.23ꢀ7.27 (m, 1H); 7.69 (bt, J = 4.6
Hz, 1H); 7.71 (d, J = 8.2 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ
1H); 7.72 (d, J = 8.3 Hz, 1H); 9.33 (bs, 1H). 13C NMR (CDCl3,
125 MHz) δ 15.3, 15.9, 26.5, 27.2, 29.4, 31.3, 35.9, 39.6, 40.1,
42.3, 45.3, 55.6, 56.4, 57.3, 63.4, 112.0, 115.9, 116.5, 118.2,
119,1 125.4, 128.2, 132.8, 133.1, 133.4, 152.4, 155.0, 177.9;
15.3, 25.5, 26.4, 31.0, 35.9, 40.0, 40.3, 43.7, 45.5, 55.6, 56.5, 75 HRMS (ESI): m/z calcd. for C29H43N6O3: [M+H]+, 523.3391;
59.3, 63.1, 111.9, 116.0, 116.4, 118.1, 118.7, 125.3, 128.2, 132.8,
20 133.6, 152.5, 173.6; HRMS (ESI): m/z calcd. for C26H38N5O2:
[M+H]+, 452.3020; found: 452.3019.
found: 523.3385.
Acknowledgements
(6aR,9R,10aR)ꢀ7ꢀallylꢀN9ꢀ[3ꢀ(dimethylamino)propyl)ꢀN4ꢀ
ethylꢀN9ꢀ(ethylcarbamoyl)ꢀ6a,7,8,9,10,10a[hexahydroindoloꢀ
[4,3ꢀfg]ꢀquinolineꢀ4,9(6H)ꢀdicarboxamide (C) and regioisoꢀ
25 mer (6aR,9R,10aR)ꢀ7ꢀallylꢀN9ꢀ[(3ꢀ(dimethylamino)propyl)carꢀ
bamoyl]ꢀN4,N9ꢀdiethylꢀ6a,7,8,9,10,10aꢀhexahydroindolo[4,3ꢀ
fg]quinolineꢀ4,9(6H)ꢀdicarboxamide (16) Carboxylic acid 10
(0.490 g, 1.33 mmol) in an oven dried glassware, under N2
atmosphere was suspended in anhydrous DCM (8 mL). TEA
30 (0.37 mL, 2.66 mmol) and EDCꢁHCl were added and reaction
mixture was stirred for 23 h. at room temperature. After that
reaction was stopped with addition of H2O (30 mL) and solution
was extracted with DCM (2x30 mL). Combined organic phases
were concentrated under reduced pressure and residue was
35 purified by column chromatography (pyr. : Me2CO = 10 : 90).
First the desired product, impurity C, was eluted and evaporation
of mobile phase gave titled compound as light yellowish foam
(0.405 g, 58%). Part of the foam (55 mg) was further crystallized
Financial support for this research was provided by Lek d.d., a
Sandoz Company. We would like to acknowledge Roman Burja
80 TLCM head for valuable help, Dr. Martin Črnugelj for NMR
assistance and University of Ljubljana, Faculty of Chemistry and
Chemical Technology for high resolution mass analyses and
elemental microanalyses. F. P. gratefully acknowledges The
Ministry of Higher Education, Science and Technology of the
85 Republic of Slovenia, the Slovenian Research Agency (P1ꢀ0230ꢀ
0103) and EN→FIST Centre of Excellence for their partial
financial support.
Notes and references
a Lek d.d., a Sandoz Company, Kolodvorska cesta 27, 1234 Mengeš,
90 Slovenia. Tel: +386 1 721 7206; Eꢀmail: jernej.wagger@sandoz.com
b Faculty of Chemistry and Chemical Technology, University of
Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
cEN
Slovenia
→FIST Centre of Excellence, Dunajska c. 156, 1000 Ljubljana,
o
from toluene (0.2 mL) and heptane (3 mL) at ꢀ40 C to give light
40 yellowish solid (45 mg, 82%). Rf : 0.46 (Pyr. : Me2CO = 10% :
90%); m.p. = 109ꢀ110 oC, lit.4a 125ꢀ127 oC (from diisopropyl
ether); [α]D ꢀ71.8 (c 0.19; DCM); IR: υmax 3334, 3274, 2971,
2971, 2936, 2867, 2828, 2781, 2245, 1668, 1525, 1438, 1340,
95
† Electronic Supplementary Information (ESI) available: Copies of 1H
and 13C NMR spectra of all synthetised compounds. See
DOI: 10.1039/b000000x/
‡ Footnotes should appear here. These might include comments relevant
1
1525, 1438, 1340, 1271, 1138, 913, 729 cmꢀ1; H NMR (CDCl3,
100 to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
45 500 MHz) δ 1.18 (t, J = 7.2 Hz, 3H); 1.29 (t, J = 7.2 Hz, 3H);
1.73 (m, 1H); 1.83ꢀ1.91 (m, 2H); 2.28 (s, 6H); 2.34ꢀ2.44 (m, 2H);
2.49ꢀ2.58 (m, 2H); 2.63 (t, J = 12.9 Hz, 1H); 2.79 (d, J = 11.8 Hz,
1H); 2.95 (bt, J = 8.9 Hz, 1H); 3.16 (d, J = 10.8 Hz, 1H); 3.26ꢀ
3.40 (m, 5H); 3.47ꢀ3.58 (m, 3H); 3.72ꢀ3.90 (m, 2H); 5.19 (d, J =
50 10.0 Hz, 1H); 5.25 (d, J = 17.1 Hz, 1H); 5.62 (bt, J = 5.3 Hz, 1H);
5.88ꢀ5.99 (m, 1H), 7.02 (d, J = 7.2 Hz, 1H); 7.26 (t, J = 7.7 Hz,
1H), 7.70 (d, J = 8.2 Hz, 1H); 9.45 (bs, 1H). 13C NMR (CDCl3,
125 MHz) δ 14.9, 15.3, 26.5, 29.8, 30.4, 31.3, 35.6, 36.0, 39.9,
42.3, 43.3, 44.9, 55.7, 56.2, 63.4, 111.8, 116.1, 116.6, 118.1,
55 118.7, 125.4, 128.3, 132.7, 133.5, 133.7, 152.4, 177.6; HRMS
(ESI): m/z calcd. for C29H43N6O3: [M+H]+, 523.3391; found:
523.3390.
1
2
3
4
P. Del Dotto, U. Bonuccelli, Clin. Pharmacokinet., 2003, 42, 633.
ICH Q3A Guideline, Revision 2, 2008.
European Pharmacopoeia, 7th ed. (7.5), 2012, Monograph C, pp 1535.
(a) E. Brambilla, E. di Salle, G. Briatico, S. Mantegani, A.
Temperilli, Eur. J. Med. Chem., 1989, 24, 421. (b) P. Salvati, A. M.
Caravaggi, A. Temperilli, G. Bosisio, O. Sapini, E. di Salle, U.S.
Patent, 4526892, 1985; Chem. Abstr., 1985, 103, 160754.
(a) A. Stoll, A. Hofmann, Helv. Chim. Acta, 1943, 26, 2070. (b) A.
Stoll. A Hofmann, Th. Petrzilka, Helv. Chim. Acta , 1946, 29, 635.
(c) R. Ručman, N. Djordjevič, DE Patent, 2708042, 1976; Chem.
Abstr., 1977, 88, 158466.
105
5
6
110
G. Marzoni, W. L Garbrecht, P. Fludzinski, M. L. Cohen, J. Med.
Chem., 1987, 30, 1823.
10 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 11 of 12
RSC Advances
View Article Online
DOI: 10.1039/C3RA43417F
7
8
J. v. Braun, K. Heider, E. Müller, Ber., 1918, 281.
with halogenated solvents like DCM, DCE and chlorobenzene with
the ratios of cabergoline (1) vs. regioisomer of 4.1, 4.1 and 4.7
respectively.
(a) A. M. Crider, R. Grubb, K. A. Bachmann, A. K. Rawat, J. Pharm.
Sci., 1981, 70, 1319. (b) T. A. Montzka, J. D. Matiskella, R. A.
Partyka, Tetrahedron Lett., 1974, 15, 1325. (c) Z. Časar, T. Mesar,
WO Patent, 2009133097, 2009; Chem. Abstr., 2009, 151, 528967.
E. C. Kornfeld, N. J. Bach, EP Patent, 3667, 1979; Chem. Abstr.,
1979, 92, 181450.
60
25 Ratio of C vs. 15 was determined from 1H NMR spectrum of
5
evaporated crude reaction mixture. Singlets of NMe2 at δ [ppm] 2.30
and 2.28 for C and 15 were used.
9
65 26 I. Candiani, W. Cabri, F. Zarini, A. Bedeschi, S. Penco, Synlett 1995,
10 M. Hafner, M. Sulyok, R. Schuhmacher, C. Crews, R. Krska, World
Mycotoxin J., 2008, 1, 67.
605.
27 T. Fehr, P. A. Stadler, A. Hofmann, Helv. Chim. Acta, 1970, 53,
10 11 J. Beneš, A. Černý, V. Miller, S. Kudrnáč, Coll. Czech. Chem.
Comm., 1983, 48, 1333.
2197.
12 Amount of epimerisation in transformation of 8 to 9 was determined
on the worked up, crude reaction mixture. Recording 1H NMR of the
reaction mixture showed on 6:1 epimere ratio. Triplets of
15
20
25
30
35
40
45
CH3CH2NCO at δ [ppm] 1.15 and 1.12 of 9a and 9b were used. See
supplementary information.
13 S. Ohno, Y. Adachi, M. Koumori, K. Mizukoshi, M. Nagasaka, K.
Ichihara, Chem. Pharm. Bull., 1994, 42, 1463.
14 R. Gažák, V. Křen, P. Sedmera, D. Passarella, M Novotna, B.
Danieli, Tetrahedron, 2007, 63, 10466.
15 Z.ꢀX. Wang, Y.Q. Li, M. Kondamreddy, X. Cai, U.S. Patent,
20080275240, 2008; Chem. Abstr., 2008, 149, 534450.
16 (a) S. Mantegani, E. Brambilla, C. Caccia, E. di Salle, M. A. Cervini,
R. A. McArthur, G. Traquandi, M. Varasi, Il Farmaco, 1998, 53, 65.
(b) L. Bernardi, S. Mantegani, A. Temperili, G. Traquandi, GB
Patent, 2162173, 1986; Chem. Abstr. 1986, 105, 79216.
17 K. E. Pfitzner, J. G. Moffatt, J. Am. Chem. Soc., 1963, 85, 3027.
In general DCC was used for DMSO activation, albeit more
expensive EDCꢁHCl was also employed. There were no differences
in reaction yield between the two, although aldehyde prepared using
EDCꢁHCl did not require so thorough purification with respect to the
residual urea byꢀproduct.
18 J. R. Parikh, W. v. E. Doering, J. Am. Chem. Soc., 1967, 89, 5505.
19 (a) P. A. Stadler, R. K. A. Giger, in Natural Products and Drug
Development, Krogsgaard, P. L.; Brøgger, S. C.; Kofod H., Ed.,
Munksgard: Copenhagen, 1984; pp 463ꢀ484. (b) P. M. Dewick, in
Medicinal Natural Products, John Weily and Sons, Ltd. 2002; 2nd
Ed., pp 368ꢀ376.
20 S. Inuki, A. Iwata, S. Oishi, N. Fujii, H. Ohno, J. Org. Chem., 2011,
76, 2072.
21 (a) B. O. Lindgren, T. Nilsson, Acta Chem. Scand., 1973, 27, 888. (b)
B. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron, 1981, 37,
2091.
22 (a) B. F. DeTar, R. Silverstein, J. Am. Chem. Soc., 1966, 88, 1013.
(b) J. Podlech, in HoubenꢀWeyl, Methods of Organic Chemistry,
Additional and Supplementary Volume E22a to the 4th Edition,
Synthesis of Peptides and Peptidomimetics, M. Goodman, A. Felix,
L. Moroder, C. Toniolo, Ed., Georg Thieme Verlag: Stutgart, New
York, 2001, pp. 517ꢀ533.
50 23 (a) S. W. Ashford, K. E. Henegar, A. M. Anderson, P. G. M. Wuts, J.
Org. Chem., 2002, 67, 7147. (b) A. L. Gutman, G. Nisnevich, I.
Rukhman, B. Tishin, A. Vilensky, B. Pertsikov, U.S. Patent,
20020177709, 2002; Chem. Abstr., 2002, 138, 4728. (c) J. Galambos,
L. Czibula, F. Sebõk, S. Bálint, F. Kassai, WO Patent, 2005085243,
55
2005; Chem. Abstr., 2005, 143, 286587.
24 A solvent screening was made by others (see ref. 15) with the aim to
improve the ratio of cabergoline (1) vs. its regioisomer in the reaction
of cabergolinic acid A with EDCꢁHCl. The best results were achieved
This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C3RA43417F
Synthesis of European Pharmacopoeial impurities of Cabergoline is demonstrated via two
different approaches varying in number of steps and stereochemistry.