A Fit-for-Purpose Synthesis of (R)-2-Methylazepane

Article abstract of DOI:10.1021/acs.oprd.9b00425

The preparation of new RSV inhibitors required an efficient synthesis of (R)-2-methylazepane ((R)-1) amenable to large-scale production to support preclinical studies. After consideration of different options, an efficient five-step synthesis relying on t

Full text of DOI:10.1021/acs.oprd.9b00425

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Full Paper
A fit for purpose synthesis of (R)-2-methyl-azepane
Sylvain Guizzetti, Antoine Michaut, Guillaume Federspiel, Julien Eymard, Isabelle Caron,
Sabrina Quatrevaux, Etienne Daras, Sandrine Jolly, Jerome Guillemont, and David Lançois
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00425 • Publication Date (Web): 12 Dec 2019
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A fit for purpose synthesis of (R)-2-methyl-azepane
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Sylvain Guizzetti, †* Antoine Michaut, ‡ Guillaume Federspiel, † Julien Eymard, ‡ Isabelle
Caron, ‡ Sabrina Quatrevaux, ‡ Etienne Daras, † Sandrine Jolly, ⸸ Jérôme Guillemont, ⸸
David Lançois⸸
†NovAliX, Bio Parc, 850 boulevard Sébastien Brant BP 30170
67405 Illkirch-Graffenstaden CEDEX – France
‡ NovAliX on-site Janssen-Cilag. Centre de recherche Pharma Campus de Maigremont.
BP615 27106 Val-de-Reuil CEDEX – France
⸸ Janssen R&D, Domaine de Maigremont – CS10615
27106 Val de Reuil Cedex France
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ABSTRACT
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Preparation of new RSV inhibitors required an efficient synthesis of (R)-2-methyl-azepane
amenable to large-scale production to support preclinical studies. After consideration of
different options, an efficient five-step synthesis relying on the preparation of the racemic
N-Boc precursor and its purification by chiral SFC was developed and successfully
implemented on four hundred gram-scale.
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KEYWORDS: RSV inhibitors, (R)-2-methyl-azepane, Chiral SFC, route scouting
INTRODUCTION
During the course of a project aiming at finding new Respiratory Syncytial Virus (RSV)
inhibitors,1 the 2-methyl-azepane motif 1 appeared to be one of the most promising sub-
units of the newly discovered preclinical drug candidates.2 Consequently, a larger quantity
of the enantiomerically pure (R)-1 key intermediate was required for further in-vivo
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biological evaluation. In this report, we detail the route evaluation and the successful
synthesis of the targeted key intermediate on multi hundred-gram scale.
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RESULTS AND DISCUSSION
Chiral amines are key structural motifs found in many natural products as well as
pharmaceuticals, agrochemicals and fine chemicals.3 A host of chemical methods have
been developed to access this highly sought-after class of compounds.3b,4 Nevertheless,
only a very limited number of synthetic options are available for the particularly
challenging 2-methyl-azepane core. The groups of Turner and Kroutil have described
closely related whole-cell biocatalytic asymmetric reduction of cyclic imines5 whilst
Meyers and co-workers developed a chiral auxiliary approach using [5.3.0]-bicyclic
lactams derived from (R)-phenylglycinol.6 The former approach requires the production
of a large amount of biocatalyst and was not considered for the sake of time; the latter
was investigated but quickly abandoned because of low yields and inadequate
enantiopurity, as described in the original paper. In addition to asymmetric reactions,
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chiral hydroxamic acid-catalyzed kinetic resolution was described by Hsieh and co-
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The key building block 4 was initially prepared as a racemate from which the two
enantiomers were found to be readily separated by preparative chiral supercritical fluid
chromatography (SFC) with an excellent enantiopurity (99% e.e. by chiral HPLC). The
(R)-enantiomer was later established as the lead to one of the candidates with the best
in-vitro activity. Because of time pressure, the decision was taken to rely on the efficiency
of the previously developed chiral separation and to find a viable synthesis that would
enable consistent and timely delivery of the racemic N-Boc precursor 4.
The original synthetic route (scheme 1) relies on the deprotonation of N-Boc protected
azepane 3 under cryogenic conditions8 and was hampered by irreproducibility and a
tedious purification of (±)-4 from unconverted 3. Although we were able to overcome the
reproducibility problem and consistently achieved conversions of greater than 95%
through water removal from 3 by azeotroping with toluene, chromatographic purification
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produces compound (±)-4 in low yields. This pathway was then deemed unpracticable
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for implementation on a large scale.
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Scheme 1: Initial synthetic route towards (R)-2-methyl-azepane 1a
Boc
Boc
Boc
H
H
N
(R)
(b)
(a)
(c)
(d)
N
N
N
N
(R)
1
(R)-
2
3
4
4
(R)-
()-
a: reagents and conditions: (a) Boc2O, DCM, 0 °C to RT, 2 h, 100%; (b) (i) sec-BuLi,
TMEDA, CPME, -78 °C to -40 °C (ii) Me2SO4, -78 °C to 0 °C, 90 min, 50% (c) Chiral SFC,
45%; (d) aq. HCl, MeOH, 94%.
Alternative synthetic approaches to compound 1 are described in the literature. Beside
route A and two reports in which the target is obtained as a minor component of the
reaction mixture,9 three main strategies have been disclosed from commercially available
starting materials (scheme 2). Routes B10 and C6,11 rely on a rearrangement respectively
from cyclohexanone 6 and 2-methylcyclohexanone 10 whilst routes D12 and E13 proceed
through the alkylation of an N-protected ɛ-caprolactam.14
Scheme 2: Overview of the described strategies towards racemic 2-methyl-azepane 1
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H
N
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Boc
HN
O
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9
Route E
alkylation of
N-Boc lactam
Route A
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17
O
O
H
N
N
NH
Route B
Beckmann
rearrangement/
alkylation
Route D
alkylation of
N-TMS lactam
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14
-1
()
Route C
Schmidt or Beckmann
rearrangement
O
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Route E was ruled out because of the low reported yield and its overall similarity to route
D with one additional step. The feasibility and practicability of the three remaining routes
were assessed experimentally (scheme 3) with the objective of identifying a route that
could be easily scaled-up. The route did not need to fulfill all the criteria of a commercial
process at this stage of the drug discovery program, but having the potential to be
developed further would be desirable.
Scheme 3: Explored synthetic pathways towards racemic 2-methyl-azepane 1a
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Route B
HO
MsO
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O
N
N
N
(b)
(a)
(c)
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Route D
O
O
H
N
TMS
(i)
(h)
(j)
N
NH
N
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9
-1
()
(f)
Route C
OH
O
O
H
N
O
N
(e)
(d)
NH
+
10
-11
(g)
12
13
(E)
a: reagents and conditions: (a) NH2OH, NaOAc, i-PrOH, RT, 30 min, 92%; (b) MsCl,
Et3N, DCM, -20 °C, 10 min, 100%; (c) AlMe3, Toluene/DCM, -78 °C to 0 °C, 2 h then
DibalH, DCM, 0 °C, 2 h, 62%. (d) NH2OH, NaOAc, i-PrOH, 60 °C, 60 min, 66%; (e) NaOH,
PhSO2Cl, acetone, 0 °C to RT, 16 h, 44%; (f) LiAlH4, THF, reflux, 2 h then HCl
(3M/CPME), 0 °C to RT, 1 h, 73%. (g) ref 6: aq HCl, NaN3, 0 °C; (h)-(j) see scheme 4
Route B relies on a well-documented organoaluminum promoted tandem Beckmann
rearrangement15 followed by alkylation.5c The results obtained were in line with the
described procedures. This pathway was demonstrated to provide short and efficient
access to the target compound in an overall yield of 25% over 3 steps. Nevertheless,
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safety issues with trimethylaluminum16 and the cumbersome work-up associated with its
hydrolysis prevent the scalability of this sequence.
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Route C was seen as advantageous as it avoids the requirement for an organometallic
reagent but the initial protocol relying on a Schmidt rearrangement6 poses a serious safety
concern as large quantities of hydrazoic acid are generated.17 Based on our previous
experience, a Beckmann rearrangement15 was envisaged as a safer alternative. A quick
screening of reaction conditions (Table S1) identified the combination of sodium
hydroxide and benzenesulfonyl chloride as an efficient promoter for the transformation of
oxime (E)-11 into 12.18 Unfortunately, despite the careful removal of (Z)-11, the crude
reaction mixture contained 10 mol% of the regio-isomer 13 whose separation from 12
was feasible but time consuming and detrimental to the yield.
On the other hand, the feasibility of the key step of route D, methyllithium addition on
1-trimethylsilyl-azepan-2-one 15,12 was quickly demonstrated. Minimal optimization
focusing on the reduction of imine 9 and isolation of 2-methyl-azepane 1 (table S2) was
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performed. Interestingly, a palladium-catalyzed hydrogenation was substituted for
stoichiometric aluminum-reagent based reduction.
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One major advantage of route D is the ease of purification of the different intermediates
with only N-Boc-2-methyl-azepane 4 requiring chromatography prior to the chiral
separation. Indeed, the first intermediate, 1-trimethylsilylazepan-2-one 15, was purified
by distillation while imine 9 resulting from methyllithium addition was passed without
purification to the hydrogenation step. Although, racemic 2-methyl-azepane 1 as a free
base is volatile (b.p. = 150v°C at 760 mmHg)12 and could have been distilled, it was found
that hydrochloride formation followed by trituration from an ethereal solvent efficiently
purged most of the by-products (mainly ɛ-caprolactam and trimethylsilyl derivatives) at
that stage.
Scheme 4: large-scale preparation of (R)-2-methyl-azepanea
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O
O
H
TMS
(b)
(a)
(c)
N
N
NH
N
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9
-1
()
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Boc
Boc
H
N
(R)
(d)
(e)
(f)
N
N
(R)
1
(R)-
4
4
(R)-
()-
a: reagents and conditions: (a) TMSCl, Et3N, toluene, 40 °C, 4 h, 85%; (b) MeLi, CPME,
-30 °C to 22 °C, 3 h (c) H2, Pd/C, EtOH/CPME, 22 °C, 18 h then HCl (4N/CPME), 54%
over 2 steps (d) Boc2O, Et3N, 22 °C, 3 h then NaOH, DMAP, 22 °C, 1 h, 67% (e) Chiral
SFC, 45%; (f) aq. HCl, MeOH, 94%.
The developed five-step sequence was successfully scaled up on 400 g-scale of 1-
trimethylsilylazepan-2-one 15 (scheme 4) delivering (R)-2-methyl-azepane in a 13%
overall yield. Although satisfactory for the rapid delivery of intermediate 1 for biological
testing, further development of the current synthetic protocols would be needed before
implementation on a full manufacturing scale. In particular, the development of an
asymmetric method for reducing imine 9 is envisioned as a potential breakthrough since
it would avoid the loss of half of the synthesized material and circumvent the protecting
manipulation steps.
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CONCLUSIONS
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Comprehensive route scouting allowed the identification of an efficient and readily
scalable synthesis of (R)-2-methyl-azepane. The key racemic intermediate could be
obtained in four steps from ɛ-caprolactam with only one chromatographic purification on
a 400 g-scale. Subsequent purification by chiral SFC and deprotection afforded the
enantiopure compound in high yield within a short cycle time. Further development efforts
should focus asymmetric reduction of intermediate imine 9.
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EXPERIMENTAL SECTION
General procedures. NMR experiment was carried out using a Bruker Avance 500 spectrometer
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equipped with a reverse triple-resonance (1H, C, N TXI) probe head with z gradients and
operating at 500 MHz for the proton and 125 MHz for carbon or carried out using a Bruker Avance
DRX 400 spectrometer at ambient temperature, using internal deuterium lock and equipped with
reverse double-resonance (1H, 13C, SEI) probe head with z gradients and operating at 400 MHz for
the proton and 100 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J
values are expressed in Hz. The following abbreviations were used to indicate multiplicities: s =
singlet; d = doublet; t = triplet; q = quartet; m = multiplet. Chemical yields refer to pure isolated
product. Unless otherwise stated, all reagents were commercially purchased and used without
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further purification. All solvents were purchased dry over molecular sieve from Aldrich or Acros
and used without further drying or purification.
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Synthesis of 1-trimethylsilyl-azepan-2-one (15). To a solution of ɛ-caprolactam 14 (1 eq.,
400 g, 3534.82 mmol) and triethylamine (1.25 eq., 447.72 g, 615 mL, 4.42 mol) in dry
toluene (2.2 L) in a 10 L-double jacketed reactor under mechanical stirring (500 rpm) was
added at 22 °C via an addition funnel chlorotrimethylsilane (1.11 eq., 428 g, 500 mL, 3.94
mol) over 40 min (internal temperature < 25 °C). At the end of the addition, the reaction
mixture was stirred at 40 °C for 4 h. The reaction was cooled to 22 °C and diluted with a
mixture of diethyl ether/heptane (1:1; 7L). The precipitate was filtered off and the filtrate
was evaporated to dryness. The residue was purified by distillation under vacuum (bath
temperature 135 °C; 8.10-1 mbar) to afford 1-trimethylsilyl-azepan-2-one (15) (556.8 g,
85%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ ppm 3.20 (m, 2 H); 2.52 (m, 2
H); 2.45 (m, 2 H); 1.73 - 1.65 (m, 4 H); 1.59 - 1.53 (m, 2 H); 0.18 (s, 9 H) 13C NMR (100
MHz, CDCl3) δ ppm 183.48 (s, 1 C) 44.68 (s, 1 C) 38.01 (s, 1 C) 30.55 (s, 1 C) 30.00 (s,
1 C) 23.66 (s, 1 C) 0.25 (s, 1 C).
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Synthesis of (±)-2-methyl-azepane ((±)-1). To a solution of MeLi (3.1M in DME, 1.3 eq., 1
L, 3.1 mol) previously cooled to -30 °C in a 10 L-double jacketed reactor, was added via
an addition funnel a solution of compound 15 (1 eq., 440 g, 2.37 mol) in CPME (1.55 L)
over 45 min (internal temperature < -15 °C). The reaction mixture was stirred at -30°C
for 30 min then at 22°C for 1 h. The reaction was quenched with NH4Cl solution (0.5M in
water, 5.5 L). The reaction was stirred at room temperature for 1 hour. The aqueous layer
was extracted with dichloromethane (3 x 1 L) The organic layers were combined, dried
over sodium sulfate, filtered and evaporated to dryness. The crude reaction mixture was
dissolved in a mixture of cyclopentyl methyl ether (1.5 L) and ethanol (800 mL) and purged
3 times with argon. Palladium on carbon (10% dry basis, 66 g) was added before the
reaction mixture was purged 3 times with hydrogen. The reaction mixture was stirred at
RT for 20 h under hydrogen (1 atm), then filtered on Celite®. The filtrate was transferred
in a 10 L-double jacketed reactor, cooled to 15 °C then hydrochloric acid (4M in
cyclopentyl methyl ether, 1.7 eq., 1 L, 4 mol) was slowly added (over 10 min) and the
reaction was stirred at 22 °C for 30 min. The suspension was evaporated to dryness and
triturated from diethyl ether (3 x 1.5 L) to afford (±)-2-methyl-azepane ((±)-1) (208 g;
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contaminated with 7 wt wt %of ɛ-caprolactam 14, 54% corrected yield) as a pink solid.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (br s, 1 H) 8.99 (br s, 1 H) 3.17 - 3.36 (m, 1 H)
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2.89 - 3.12 (m, 2 H) 1.42 - 1.91 (m, 8 H) 1.26 (d, J=6.6 Hz, 3 H) C NMR (126 MHz,
DMSO-d6) δ ppm 54.15 (s, 1 C) 44.31 (s, 1 C) 33.07 (s, 1 C) 26.64 (s, 1 C) 24.62 (s, 1 C)
24.53 (s, 1 C) 20.23 (s, 1 C).
Synthesis of (±)-N-Boc-2-methyl-azepane ((±)-4). To a suspension of compound (±)-1 (1
eq., 207 g, 1.38 mol) in DCM (1.15 L) was added triethylamine (1.2 eq., 167.44 g, 230
mL, 1.65 mol) then a solution of di-tert-butyl dicarbonate (1.1 eq., 332 g, 1.52 mol) in DCM
(300 mL) was added slowly. The reaction mixture was stirred at 22 °C for 3 h then
quenched with NaOH (7.5M/H2O; 1.63 eq., 300 mL, 2.25 mol) and 4-
(dimethylamino)pyridine (0.0015 eq., 0.8 g, 2 mmol) and stirred at 22 °C for 1 h. The
aqueous layer was extracted with DCM (2 x 300 mL). The organic layers were combined,
washed with NaOH 0.5M (2 x 100 mL), dried over sodium sulfate, filtered and evaporated
to dryness. The residue was then purified by flash chromatography (SiO2, cyclohexane /
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DCM 100:0 to 80:20) to afford (±)-N-Boc-2-methylazepane ((±)-4) (215.6 g; contaminated
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with 8wt % residual dichloromethane, 67%).
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Purification of (R)-N-Boc-2-methyl-azepane ((R)-4). 63.8 g of compound 4 were purified via
chiral SFC (Stationary phase: Whelk O1 (S,S) 5µm 250 x 21.1mm, Mobile phase: 2.5% Heptane,
95% CO2, 2.5% i-PrOH). The fractions containing pure (S)-4 were combined and evaporated in
vacuo to afford (S)-4 (30.6 g, 48%). The fractions containing pure (R)-4 were combined and
1
evaporated in vacuo to afford (R)-4 (28.6 g, 45%). Mixture of rotamers (55:45) H NMR (400
MHz, DMSO-d6) δ ppm 3.98 (dt, J=11.9, 6.2 Hz, 0.55 H); 3.86 (dt, J=11.7, 6.0 Hz, 0.45 H); 3.57
(br d, 0.45 H); 3.49 (br d, 0.55 H); 2.69-2.77 (m, 1 H); 1.86 - 1.97 (m, 1 H); 1.58 - 1.73 (m, 3 H);
1.39 (s, 9 H); 1.00-1.40 (m, 4 H); 1.00 (d, J=6.6 Hz, 1.35 H); 0.96 (d, J=6.6 Hz, 1.65 H) 13C NMR
(126 MHz, DMSO-d6) δ ppm 154.87 (s, 1 C) 78.31 (s, 1 C) 78.18 (s, 1 C) 62.43 (s, 1 C) 51.72 (s,
1 C) 50.48 (s, 1 C) 40.89 (s, 1 C) 40.47 (s, 1 C) 35.83 (s, 1 C) 35.66 (s, 1 C) 29.50 (s, 1 C) 29.30
(s, 1 C) 28.51 (s, 1 C) 25.85 (s, 1 C) 25.72 (s, 1 C) 25.42 (s, 1 C) 20.34 (s, 1 C) 19.93 (s, 1 C) .
Synthesis of (R)-2-methyl-azepane ((R)-1). In a 5 L-double jacketed reactor with
mechanical stirring, aqueous HCl 37% (639 mL; 7.65 mol) was added dropwise (with
monitoring of internal temperature 15 °C < T < 23 °C) to a solution of compound (R)-4
(510 g; 2.39 mol) in MeOH (1 L). The reaction mixture was stirred at room temperature
for 18 h and evaporated to dryness. The residue was azeotroped with EtOH (4 x 250 mL)
then with Et2O (250 mL) to give a white solid. The solid was taken up in Et2O (250 mL)
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and the precipitate was filtered off, washed with Et2O (4 x 200 mL) and dried under
vacuum at RT for 18 h to give 336 g of pure (R)-2-methyl-azepane hydrochloride (94%).
1H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (br s, 1 H) 8.99 (br s, 1 H) 3.17 - 3.36 (m, 1 H)
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2.89 - 3.12 (m, 2 H) 1.42 - 1.91 (m, 8 H) 1.26 (d, J=6.6 Hz, 3 H) C NMR (126 MHz,
DMSO-d6) δ ppm 54.15 (s, 1 C) 44.31 (s, 1 C) 33.07 (s, 1 C) 26.64 (s, 1 C) 24.62 (s, 1 C)
24.53 (s, 1 C) 20.23 (s, 1 C) [α]D20: +8.52° (c 0.27 in DMF)
ASSOCIATED CONTENT
Supporting Information.
The following files are available free of charge. Table describing the conditions
screened for the synthesis of compounds 12 and (±)-1 via route D, experimental
procedures for routes A, B, and C, and analytical data for compounds (R)-1, (±)-1, (R)-
4, 7, 8, (E)-11, 12, 15 (PDF).
AUTHORS INFORMATION
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Corresponding Author
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*Email: sguizzetti@novalix.com.
ORCID
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Sylvain Guizzetti: 0000-0003-4656-2431
Author Contributions
All authors contributed to the preparation of the manuscript and approved the final
version.
Funding Sources
This research was financially supported by Janssen R&D and NovAliX.
Notes
The authors declare no competing financial interest. A patent application has been filed
by some of the co-authors (David Lançois, Jérôme Guillemont, Antoine Michaut)
regarding the use of the described compound as intermediate for the synthesis of new
RSV inhibitors.
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ACKNOWLEDGMENT
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The authors acknowledge Frank Moffatt for careful proof-reading of the manuscript and
Julien Marin for support throughout all the project.
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