Practical Synthesis of a 6-Triazolylazabicyclo[3.1.0]hexane

Article abstract of DOI:10.1021/acs.oprd.8b00101

We describe a practical, scalable synthesis of an advanced heterocyclic intermediate, (1R,5S,6s)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane. A robust synthetic sequence based on a Kulinkovich-de Meijere pyrroline cyclopropanation followed by tran

Full text of DOI:10.1021/acs.oprd.8b00101

Article
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
pubs.acs.org/OPRD
Practical Synthesis of a 6‑Triazolylazabicyclo[3.1.0]hexane
,
†
,†
Lauren E. Sirois,* Jie Xu,* Remy Angelaud, David Lao, and Francis Gosselin
Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United
States
*
S Supporting Information
ABSTRACT: We describe a practical, scalable synthesis of an advanced heterocyclic intermediate, (1R,5S,6s)-6-(4H-1,2,4-
triazol-4-yl)-3-azabicyclo[3.1.0]hexane. A robust synthetic sequence based on a Kulinkovich−de Meijere pyrroline
cyclopropanation followed by transamination of N,N′-dimethylformamide azine with the resultant amine was developed to
supply >18 kg of the target triazolyl azabicycle with 98 wt % purity in its free base form. Reaction conditions and isolation
methods for the key 1,2,4-triazole formation step were explored to minimize undesired reaction pathways and to increase the
purity of the product. Additionally, at several stages different freebasing methods were implemented that addressed the high
water solubility of the associated nitrogen-rich compounds.
INTRODUCTION
poisoning were observed in Pd-catalyzed couplings, likely
stemming from the presence of unidentified impurities carried
through the synthesis.
Unfortunately, the solubility profile of 2·2HCl (vide infra)
provides limited options to upgrade its purity via recrystalliza-
tion, and thus, controlling the quality of upstream intermediates
such as 6 became imperative. It was also envisioned that an
improved synthetic process would instead target the free base,
■
The 1,2,4-triazole nucleus is featured in a variety of biologically
and medicinally interesting molecules, and bicyclic scaffolds
such as [3.1.0]hexane architectures allow for tunable display of
this pharmacophore within a protein target of interest. Because
of the incorporation of a pyrrolidine moiety, (1R,5S,6s)-6-(4H-
,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane (2) in particular
can serve as a key intermediate toward a diverse range of
synthetic targets (including active pharmaceutical ingredients)
1
1
2
, as an isolated solid, which was found to perform better in
metal-catalyzed couplings. Finally, while the building blocks 4
and 5 are commercially available on moderate scale (generally
via any number of C−N cross-coupling or S Ar displacement
N
reactions (Scheme 1). To support the production of such
promising lead molecules, we developed and executed a fit-for-
purpose kilogram-scale synthesis of exo-triazolyl azabicycle 2.
1
−10 kg), consideration toward long-term cost and supply of 2
prompted evaluation of their preparation on a larger scale.
In our retrosynthetic analysis, construction of the 4H-1,2,4-
2
triazole by cyclization onto a suitably protected exo-6-amino-
Scheme 1. General Reactions of (1R,5S,6s)-6-(4H-1,2,4-
Triazol-4-yl)-3-azabicyclo[3.1.0]hexane (2), a Versatile
Building Block
bicycle 7 followed by pyrrolidine deprotection would still be
performed in the end game of the synthesis. We further
considered three general pathways for installation of the
3
primary amine: (A) reduction of a nitro group; (B) Curtius or
Hofmann rearrangement from the carboxylic acid; and (C)
direct installation from a formamide during a Kulinkovich−de
4
Meijere cyclopropanation (Scheme 3). If not derived from
5
route C, the 3-azabicyclo[3.1.0]hexane scaffold could be
constructed via either cyclopropanation of a 3-pyrroline
(
(
route B1) or conjugate addition/elimination to a maleimide
routes A and B2) or an acyclic Michael acceptor (route B3).
Ultimately, we sought to avoid inherently hazardous
Discovery Synthesis and Retrosynthetic Analysis. In
our discovery laboratories, a viable route to 2 was first explored
on a multigram scale, proceeding from transamination of an
excess (500 mol %) of N,N′-dimethylformamide azine (4,
DMFA) onto tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]-
hexane-3-carboxylate (5) in the presence of p-toluenesulfonic
acid (p-TsOH) (Scheme 2). Triazole 6 was then telescoped
crude or taken forward with minimal silica gel chromatographic
purification into an acid-mediated Boc deprotection to provide
the dihydrochloride salt 2·2HCl in ∼70% overall yield (from 5)
with ∼80 wt % purity. While this route was successful in
delivering material for initial development, the low and variable
purity of 2·2HCl derived from this sequence impeded
development of subsequent transition-metal-catalyzed C−N
bond-forming reactions. Indeed, several instances of catalyst
chemistry such as Raney nickel reduction and the use of
bromonitromethane (route A) and handling of diazoacetate
3
(
route B1). The selectivity for the exo isomer during Rh-
6
catalyzed cyclopropanation (route B1) is known to be modest
(
been demonstrated to proceed with endo selectivity or to
require additional isomerization/redox chemistry (route B2)
or more complex substrates (route B3). Finally, while safety
concerns surrounding Curtius and Hofmann rearrangements
∼3:1 exo:endo), and Corey−Chaykovski-type reactions have
7
8
Received: April 5, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00101
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Article
Scheme 2. Discovery Chemistry Route to Triazolyl Azabicycle 2·2HCl
Scheme 3. Retrosynthetic Analysis of 2
Scheme 4. Assembly of 5
Scheme 5. Synthesis of 4
can be mitigated by performing thorough reaction safety testing
and/or through continuous processing, the additional develop-
the event, the sequence shown in Scheme 4 was carried out
with a slight modification of the literature procedures in 32%
isolated yield over two steps, providing exo-5 as a low-melting
9
ment required and the other drawbacks mentioned for routes A
and B steered us to investigate route C as the expedient choice
14
semisolid from 100 kg of 20.
10
for short-term production and future optimization.
Installation of the 1,2,4-triazolyl moiety was set to follow a
transamination sequence reported by Bartlett and Humphrey
and expanded by others using either the free base or the
RESULTS AND DISCUSSION
■
15
dihydrochloride salt of DMFA (4 or 4·2HCl). Production of
DMFA has been described following a number of different
Synthesis of Precursors 4 and 5. The aza-Kulinkovich−
11
12
de Meijere cyclopropanation of N-Boc-3-pyrroline (20) in
1
6
methods.
The procedure originally adopted in our
particular had been described previously, with a reported 98:2
11c
13
11c
laboratories (Scheme 5), from 1,2-diformylhydrazine via the
intermediacy of a (chloromethylene)dimethylammonium (Vils-
meier) reagent, provided a reasonably clean reaction profile and
simple filtration for the isolation of 4·2HCl. We found that we
diastereoselectivity for the exo isomer in 76−90% yield.
Reaction with N,N-dibenzylformamide (19) allows for
orthogonal deprotection via hydrogenolysis to provide our
desired 3-N-Boc-exo-6-amino-3-azabicyclo[3.1.0]hexane (5). In
B
DOI: 10.1021/acs.oprd.8b00101
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Article
could shorten the reaction time to ∼4 h on lab scale, versus 2−
Scheme 6. Possible Reaction Pathways in the
Transamination toward Triazole 6
1
5b
3
days at 10 °C, by warming the reaction mixture to 40 °C
(
conditions A). However, a reaction calorimetry study indicated
that addition of SOCl to a mixture of 1,2-diformylhydrazine
2
(
10 g) in DMF over 30 min at 0 °C generated an exotherm (a
large adiabatic temperature rise of approximately 100 °C) and a
potential accumulation of unreacted SOCl . We therefore
2
implemented an addition-controlled protocol in which SOCl2
was added to the reaction mixture at 15−25 °C over 6 h before
heating to 35−40 °C (conditions B). In this way the reaction
was safely conducted over ∼14 h for production on a >200 kg
scale (89% yield).
Liberation of the free base DMFA 4 from its dihydrochloride
15
salt proved to be challenging. As previously reported, 4·2HCl
can be neutralized with aqueous Na CO , with the drawback
2
3
that extensive extractions (e.g., a continuous process using Et O
2
for 2 days) must be employed for recovery of 4 (Scheme 5,
conditions C). A solubility screen confirmed that both 4 and 4·
2HCl are highly soluble in water, while in most organic solvents
the free base 4 exhibits high solubility (>100 mg/mL) and the
17
salt 4·2HCl almost none (<1 mg/mL). As a result, we sought
alternative nonaqueous freebasing conditions. Also previously
18
reported was a protocol using NaOEt in EtOH. This slurry-
to-slurry reaction gives a high recovery of 4 (conditions D).
However, it was found that incomplete removal of residual base
from this process could impede the downstream acid-catalyzed
transamination reaction (vide infra). Although a solvent swap
from EtOH to MTBE followed by filtration could resolve this
issue, the inefficiency led us to develop a third alternative.
give a messy reaction profile and a low assay yield (Table 1,
entries 1−3). While 1 mol % HCl was effective in promoting
a
Table 1. Catalyst Screening for the Triazole Formation
When K CO3 in toluene was employed at 60−90 °C
2
(
conditions E), free base 4 could be isolated by filtering off
inorganic solids and then concentrating the filtrate to dryness
conv.
b
yield
b
purity c
(
85% yield; Scheme 5) or telescoping the toluene solution into
entry
DMFA
catalyst (loading)
none
(%)
(%)
(area %)
the transamination reaction.
d
1
2
4·2HCl
4·2HCl
100
100
28
33
68
69
Triazole Formation and Downstream Processing.
Considerably more effort was put into further development
of the transamination reaction of 4 and 5 to install the 1,2,4-
d
d
iPr NEt
2
(
10 mol %)
3
4·2HCl
p-TsOH
100
21
61
18
triazole. On the basis of previous mechanistic discussion, we
postulated that the reaction could follow a variety of different
pathways, whereby sequential elimination of dimethylamine
(10 mol %)
e
4
5
4
4
HCl (1 mol %)
92
58
67
83
88
p-TsOH
100
(
10 mol %)
(
leading to the desired triazole 6) competes with hydrolysis
6
7
8
4
4
p-TsOH
100
94
67
69
76
87
77
88
and/or extrusion of triazine 24 to produce off-cycle compounds
such as 25 and 26 (Scheme 6a). It was also observed that the
extruded 24 could react in a transamination with further
equivalents of DMFA, thereby requiring a large excess of the
latter and/or diminishing the yield (Scheme 6b). Evidence of
these impurities, side products, and intermediates was observed
by means of mass spectrometry (e.g., 25, 26) and/or NMR
spectroscopy (e.g., 27). With an eye toward reducing these
undesired reactions and, more importantly, purging any
impurities that might form, we screened a number of different
reaction parameters, such as solvent, temperature, additives,
and relative stoichiometry of 4 versus 5.
(
3 mol %)
p-TsOH
(1 mol %)
f
4
p-TsOH
100
(
3 mol %)
a
Unless noted, all reactions were carried out on a 1.0 g scale (5.0
mmol) with DMFA (130 mol %) and toluene (7 mL/g) for 16−22 h.
The conversions reflect disappearance of 5. The assay yields of 6 were
determined by HPLC analysis of reaction/workup solutions. HPLC
area percent for 6 at the end of the reaction (excluding integration of
). 150 mol % 4·2HCl. HCl (4 M in 1,4-dioxane). Slow addition of
b
c
d
e
f
4
4
over 30−60 min.
Among the various solvents screened at 80 °C (including 2-
MeTHF, CH CN, toluene, iPrOAc, EtOAc, and CPME), the
3
reaction outcomes were similar (68−78% conversion of 5 over
the reaction of free base 4 (entry 4), the reaction profile was
observed to be cleaner overall and higher-yielding with the
originally reported p-TsOH, the loading of which could be
lowered to ca. 1−3 mol % without a negative impact on the
assay yield (entries 5−7). The addition mode of different
reaction components was also studied: slow addition of DMFA
into the solution of 5 resulted in a slightly higher assay yield
4
h). To allow for the possibility of telescoping a solution of
free base DMFA 4 from the previous reaction, toluene was
chosen for further transamination process development.
Promisingly, in toluene at 100 °C, the loading of 4 could be
reduced from 500 mol % to 130−150 mol %. Several catalysts
were also examined. A direct reaction with 4·2HCl, with or
without additional p-TsOH or Hunig’s base, was confirmed to
19
(entry 8). Gentle sparging of the reaction mixture with N2
C
DOI: 10.1021/acs.oprd.8b00101
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Article
was also implemented to help displace any dissolved dimethyl-
amine and drive the equilibrium toward 6.
Scheme 8. Preparation of Free Base 2 from 2·2HCl Using
NaOH
In the original workup procedure, a crude concentrate of 6
was taken forward after excess DMFA was removed via aqueous
citric acid washes; however, several back extractions using
EtOAc and CH Cl were also necessary to minimize product
2
2
2
0
loss. A solvent screen for 6 (Table 2) indicated that toluene
Table 2. Solubility Screening for Triazole 6
Table 3. Solubility of Free Base 2 and Its Salt 2·2HCl
solubility of 6 (mg/mL)
solubilities at rt (mg/mL)
entry
solvent
at rt
at the boiling point
entry
solvent
2·2HCl
2
1
2
3
4
5
6
7
8
9
H O
>100
>100
>100
>100
>100
>100
>100
>100
55−60
<10
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
20−25
<20
1
2
3
4
5
6
7
8
9
H O
>100
10
>100
>100
75−80
30−50
<1
2
2
MeOH
MeOH
EtOH
EtOH
<1
<1
<1
<1
<1
<1
<1
<1
<1
iPrOH
EtOAc
2-MeTHF
acetone
MIBK
iPrOH
EtOAc
iPrOAc
2-MeTHF
<1
<1
CH CN
<10
<1
3
iPrOAc
toluene
MTBE
heptane
toluene
1
1
1
0
1
2
1
1
0
1
MIBK
<5
<5
1,4-dioxane
<5
<1
Table 4. Carbamic Acid Formation during Freebasing of 2·
2HCl
itself (entry 10) offered an appropriate range of solubility
between ambient and reaction temperature such that a direct
crystallization from the reaction mixture could be performed;
6
0 °C was subsequently identified as a robust seeding point.
17
Because of its high solubility in toluene, the moderate excess
of DMFA from the transamination (30 mol %) could be purged
into the crystallization filtrate without the need for aqueous
washes. On a >30 kg reaction scale, the transamination was
completed using 130 mol % DMFA and 3 mol % p-TsOH,
providing 6 in 61% isolated yield as a storable solid with >95
area % HPLC purity (Scheme 7). Treatment of 6 with HCl in
c
entry
base
2:28 ratio
a
b
b
2
1
1
2
3
K CO3
50:50
91:9
98:2
2
K PO4
3
K PO ·H O
3
4
2
a
b
2
·2HCl (1.1 mmol), MeOH (10 mL/g), base (500 mol %), 18 h. 2·
2
HCl (0.45 mmol), MeOH (10 mL/g), base (205 mol %), 18 h.
1
,4-dioxane provides access to 2·2HCl via direct filtration from
c
Determined by HPLC analysis (area %) of the isolated product.
the reaction mixture. This deprotection process was carried out
22
on a 75 kg scale with minimal optimization to give 2·2HCl in
Switching from K CO to anhydrous K PO and later the more
88% yield with >97 wt % purity (Scheme 7).
2
3
3
4
To achieve the goal of supplying 2 as a versatile building
air-stable K
3
PO
4
·H
2
O, along with implementing degassing
block, the freebasing of 2·2HCl (with measured pK values of
procedures, successively decreased the observed amount of 28
a
24
8
.9 and 3.4) was first demonstrated using a 50% aqueous
to acceptable levels (entries 2 and 3). Under the latter
conditions, a slurry of 2·2HCl was stirred in MeOH as the
corresponding free base 2 was gradually taken into solution.
Following filtration of the inorganic salts, solid 2 was
precipitated by the addition of 1,4-dioxane. The optimized
freebasing process was eventually performed on a 30 kg scale to
provide the target triazolyl azabicycle 2 in 91% yield with,
crucially, 98 wt % and 98 area % purity (Scheme 9).
NaOH solution, and 2 was recovered in 50−80% yield
following extensive extractions (>100 mL/g) with CH Cl
2
2
and CHCl (Scheme 8). This preliminary access to 2 allowed
3
us to establish a more complete solubility profile for both the
free base and its precursor salt (Table 3). Alcohol solvents
entries 2−4), MeOH in particular (entry 2), stood out in
(
providing an opportunity to exploit the differential solubility of
the two compounds in a nonaqueous protocol. However,
significant amounts of carbamic acid 28 were also observed
along with the desired free base 2 when potassium carbonate
CONCLUSION
We have developed a practical and scalable synthesis of
(1R,5S,6s)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane
■
23
was employed as the base in MeOH (Table 4, entry 1).
Scheme 7. Transamination To Construct Triazole 6 and Subsequent Boc Deprotection To Obtain Pyrrolidine 2·2HCl
D
DOI: 10.1021/acs.oprd.8b00101
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Scheme 9. Summary of the Multikilogram Synthesis of 2
(
2) (Scheme 9). Two crucial freebasing conditions were
(381 kg, 3201 mol, 300 mol %) at 15−25 °C over 6 h. The
reaction mixture was warmed to 40 °C over 2 h, stirred at 35−
40 °C for 6 h, and then concentrated at 70−80 mmHg (70−80
°C). The mixture was cooled and centrifuged, and the cake was
washed with DMF (2 × 282 kg) and toluene (2 × 252 kg) to
give 4·2HCl (307 kg, 66 wt %, 89% corrected yield) as a white
solid. Mp 240.1−241.5 °C. The crude product was taken
forward to the next step without further purification.
discovered and implemented to streamline the process and
ultimately deliver 2 as a storable, easily handled solid. The key
transamination reaction to install the 1,2,4-triazole on the
bicyclic scaffold was also studied in depth to minimize impurity
formation and to allow for direct isolation of the product via
crystallization. This process overall represents a significant
improvement over the previous synthesis, which gave the salt 2·
2
HCl with <80 wt % purity. The chemistry was implemented
N,N′-Dimethylformamide Azine (4). To a stirred
successfully to produce >18 kg of 2 in 15% overall yield with 98
wt % and 98 area % purity.
suspension of 4·2HCl (307 kg, 66 wt %, 946 mol, 100 mol
%) in toluene (900 L) was added K
CO (287 kg, 2082 mol,
2 3
2
20 mol %) in one charge at 20−25 °C. The resulting
suspension was stirred at 60 °C for 2 h, heated to 80 °C over 2
h, then heated to 90 °C over 2 h, and stirred at 90 °C for 6 h.
The suspension was then cooled to 60 °C over 2 h, stirred at 60
°C for 12 h, cooled to 25 °C, and filtered. The solids were
washed with toluene (100 L), and the filtrate was concentrated
to give a solution of 4 (308 kg, 38 wt % in toluene, 85%
corrected yield), which was telescoped into the next step.
Separately, an analytical sample was concentrated to dryness,
EXPERIMENTAL SECTION
■
General. Unless otherwise noted, all of the reactions were
conducted under an inert atmosphere of N , and all of the
solvents and reagents were used as received. N,N-Dibenzylfor-
mamide (19) and N-Boc-3-pyrroline (20) were prepared from
formic acid/N,N-dibenzylamine and N,N-diallylamine, respec-
tively. CAUTION: A base scrubber was used for all reactions
2
involving SOCl . Melting points were recorded using an
2
providing 4 as a white to pale-orange solid. Mp 69.1−72.2 °C;
1
OptiMelt automated melting point system and are uncorrected.
H NMR spectra were recorded on a Bruker 400 MHz
spectrometer. Chemical shifts are reported in parts per million
H NMR (400 MHz, CDCl ) δ 7.79 (s, 2H), 2.83 (s, 12H);
3
1
16a
consistent with data for the known compound.
tert-Butyl (1R,5S,6s)-6-(N,N-Dibenzylamino)-3-
azabicyclo[3.1.0]hexane-3-carboxylate (18). To a 5000 L
reactor were charged THF (500 kg), compound 20 (100 kg, 79
1
3
relative to tetramethylsilane (δ = 0 ppm). C NMR spectra
were recorded on a Bruker (100 MHz) spectrometer with
complete proton decoupling. Chemical shifts are reported in
parts per million with the solvent resonance as the internal
standard (chloroform, δ = 77.0 ppm; dimethyl sulfoxide, δ =
9.5 ppm). HPLC analyses were performed on Agilent 1260
series instruments. High-resolution mass spectrometry
HRMS) was performed on an Agilent 6530C qTOF
wt %, 469 mol, 105 mol %), and Ti(OiPr) (160 kg, 563 mol,
4
127 mol %), and the mixture was cooled to 5−10 °C.
Methylmagnesium chloride (2.95 M in THF, 192 L, 563 mol,
127 mol %) was added over 3 h. Compound 19 (100 kg, 444
mol, 100 mol %) was charged into the reaction mixture over 45
min at 10−15 °C, and then the mixture was stirred for 15 min
and heated to 30−35 °C over 2.5 h. Cyclohexylmagnesium
bromide (2.05 M in 2-MeTHF, 914 L, 1875 mol, 422 mol %)
was added to the reaction mixture over 10 h at 30−40 °C. The
mixture was stirred at 35−40 °C for 3.5 h, then quenched with
5% aqueous citric acid (375 kg) over 4.5 h at 10−25 °C, and
stirred at 20−25 °C for 1.5 h. The organic layer was washed
with saturated brine (800 kg), concentrated, and cooled to 25
°C. The residue was diluted with petroleum ether (1000 L) and
washed with 5% aqueous citric acid (200 kg), then saturated
brine (2 × 250 kg), then water (200 kg). The solution was
3
(
instrument equipped with an electrospray ionization (ESI)
source in positive ionization mode. The samples were
introduced into the mass spectrometer using an Agilent 1290
ultraperformance liquid chromatograph with an Agilent
Extended-C18 column (2.1−50 mm, 1.8 μm) and a gradient
of 5−95% MeCN/H O (with 0.1% formic acid in both
2
channels) at a flow rate of 0.6 mL/min.
N,N′-Dimethylformamide Azine Dihydrochloride (4·
2
1
HCl). To a stirred solution of 1,2-diformylhydrazine (94.0 kg,
067 mol, 100 mol %) in DMF (956 kg) was added SOCl2
E
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dried over Na SO (100 kg), filtered, and concentrated under
was dried under vacuum at 70 °C for 24 h to afford 2·2HCl as a
2
4
reduced pressure to afford crude product 18 as a THF solution
145 kg). The solution was cooled to 25 °C, diluted with
white solid (60.2 kg, 98 wt %, 88% corrected yield). Mp 288.0−
1
(
289.5 °C; H NMR (400 MHz, DMSO-d ) δ 9.99 (br s, 2H),
6
petroleum ether (14 kg) and heptane (84 kg), cooled to 0 °C,
and stirred for 3 h. The slurry was centrifuged, and the product
cake was washed with cold heptane (2 × 60 L) to give 18 (83
9.40 (s, 2H), 4.00 (t, J = 2.4 Hz, 1H), 3.53−3.38 (m, 4H),
13
2.63−2.58 (m, 2H); C NMR (100 MHz, DMSO-d ) δ 144.0,
6
+
46.2, 33.7, 23.7; HRMS calcd for C H N [M + H] 151.0905,
7
10
4
kg, 95 area %, 71 wt %, 35% corrected yield). Mp 76.4−79.0
found m/z 151.0977.
(1R,5S,6s)-6-(4H-1,2,4-Triazol-4-yl)-3-azabicyclo-
[3.1.0]hexane (2). A 500 L reactor was charged with MeOH
1
°
C; H NMR (400 MHz, C D ) δ 7.19−7.07 (m, 10H), 3.57
6
6
(
d, J = 10.8 Hz, 1H), 3.41 (d, J = 2.4 Hz, 4H), 3.34 (d, J = 10.4
Hz, 1H), 3.16 (dd, J = 10.8, 4.8 Hz, 1H), 3.02 (dd, J = 10.4, 4.8
Hz, 1H), 1.48 (s, 9H), 1.37 (t, J = 2.4 Hz, 1H), 1.04 (br d, J =
(300 L) and then evacuated and backfilled with N (4×).
2
K PO ·H O (61.8 kg, 268 mol, 205 mol %) was added,
3
4
2
1
4.8 Hz, 2H); consistent with data for the known
followed by 2·2HCl (30.0 kg, 98 wt %, 131 mol, 100 mol %), to
create a stirred suspension. After each addition, the vessel was
1
1c
compound.
tert-Butyl (1R,5S,6s)-6-Amino-3-azabicyclo[3.1.0]-
evacuated and backfilled with N (4×). The reaction mixture
2
hexane-3-carboxylate (5). To a 1000 L reactor were charged
was stirred at 20−25 °C for 16 h, after which time the slurry
was filtered and the solids were washed with MeOH (2 × 60 L)
and discarded. The filtrate was concentrated (to 50 L), charged
18 (109 kg, 72 wt %, 207 mol, 100 mol %) and MeOH (300
kg). The reactor was evacuated and backfilled with N (4×). A
2
solution of 20% Pd(OH) /C (8.0 kg, 64.5 wt % water, 10 wt %
with CH
°C for 1.5 h. The mixture was filtered, and the solids were
washed with CH Cl /MeOH (10/1 v/v, 2 × 5 L) and
2 2
Cl (342 L) and MeOH (11 L), and stirred at 20−25
2
loading) in MeOH (80 kg) was charged into the reactor, and
the vessel was again evacuated and backfilled with N (4×).
2
2
2
Then the reactor was evacuated and backfilled with H (4×),
discarded. The filtrate was concentrated to 25 L, and then
dioxane (127 L) and MeOH (5 L) were added. The mixture
was heated to 80 °C for 1 h, then cooled to 25 °C over 5 h, and
stirred at 20−25 °C for 16 h. The slurry was filtered, and the
product solids were washed with dioxane/MeOH (95/5 v/v, 2
× 25 L) and heptane (2 × 25 L). The wet cake was dried under
vacuum at 70 °C for 8 h to give 2 as a white solid (18.2 kg, 98
2
and the mixture was heated to 55 °C over 4 h and stirred under
1
.8−2.0 MPa H at 55−65 °C for 20 h. The reactor was then
2
cooled to 30−35 °C over 30 min and purged with N (6×).
2
The mixture was filtered, and the solids were washed with
MeOH (80 kg) and discarded. A second hydrogenolysis
reaction was carried out in parallel, and the combined filtrates
were concentrated to afford 5 (104 kg, 83 wt %, 90% corrected
1
wt %, 91% corrected yield). Mp 198.4−199.7 °C; H NMR
1
yield). Mp 40.6−42.6 °C; H NMR (400 MHz, C D ) δ 3.64
(400 MHz, DMSO-d ) δ 8.54 (s, 2H), 3.31 (t, J = 2.4 Hz, 1H),
6
6
6
(
d, J = 11.2 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.25 (dd, J =
3.07 (d, J = 11.6 Hz, 2H), 2.76−2.71 (m, 2H), 2.02−1.98 (m,
2H); 13C NMR (100 MHz, DMSO-d
) δ 143.5, 47.9, 31.7,
11.2, 4.0 Hz, 1H), 3.10 (dd, J = 11.2, 4.0 Hz, 1H), 1.64 (br t, J
6
+
2
1
5.0; HRMS calcd for C H N [M + H] 151.0905, found m/z
51.0977.
=
2.0 Hz, 1H), 1.47 (s, 9H), 1.12−1.04 (br m, 2H), 0.70 (br s,
7 10 4
11c
2H); consistent with data for the known compound.
tert-Butyl (1R,5S,6s)-6-(4H-1,2,4-Triazol-4-yl)-3-
azabicyclo[3.1.0]hexane-3-carboxylate (6). To a solution
of 5 (40.0 kg, 83 wt %, 167 mol, 100 mol %) in toluene (113
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00101.
■
*
S
kg) was added p-TsOH·H O (952 g, 5.00 mol, 3 mol %), and
2
the resulting mixture was sparged with N (7.5−10.0 L/min)
2
and heated to 100 °C over 1 h. A solution of 4 in toluene (81.4
kg, 38 wt %, 217 mol, 130 mol %) was added to the reaction
mixture over 4 h. The reaction mixture was stirred at 100 °C for
Spectra of new compounds of interest and X-ray
crystallographic data for 2 (PDF)
1
6
8 h with N sparging, cooled to 60 °C over 1.5 h, seeded with
2
(400 g, 1.0 wt %), held at 60 °C for 1.5 h, cooled to 25 °C
AUTHOR INFORMATION
■
*
*
over 4 h, and stirred at 25 °C for 4 h. The slurry was then
filtered, and the cake was washed with toluene (2 × 66 L) and
heptane (2 × 66 L) to give 6 as a white solid (35.0 kg, 73 wt %,
Corresponding Authors
E-mail: sirois.lauren@gene.com.
E-mail: xu.jie@gene.com.
6
1% corrected yield), which was taken into the next step.
ORCID
Separately, an analytical sample was further dried at 70 °C for 2
1
Lauren E. Sirois: 0000-0002-1948-3749
Jie Xu: 0000-0001-6424-1055
Francis Gosselin: 0000-0001-9812-4180
Author Contributions
L.E.S. and J.X. contributed equally to this work.
h, providing 6 (83 wt %). Mp 107.7−110.0 °C; H NMR (400
MHz, DMSO-d ) δ 8.55 (s, 2H), 3.63 (d, J = 10.8 Hz, 2H),
6
3
(
1
.39 (t, J = 10.0 Hz, 2H), 3.30 (t, J = 2.4 Hz, 1H), 2.25−2.23
13
m, 2H), 1.39 (s, 9H); C NMR (100 MHz, DMSO-d ) δ
6
53.4, 143.3, 78.8, 47.3, 34.8, 28.1, 23.9, 23.0; HRMS calcd for
†
+
C H N O [M + H] 251.1430, found m/z 251.1503.
1
2
18
4
2
Notes
(
1R,5S,6s)-6-(4H-1,2,4-Triazol-4-yl)-3-azabicyclo-
The authors declare no competing financial interest.
[
3.1.0]hexane Dihydrochloride (2·2HCl). To a 2000 L
reactor were charged dioxane (448 L), 1-propanol (373 L), and
(98.0 kg, 76 wt %, 298 mol, 100 mol %), and the vessel was
evacuated and backfilled with N (4×). HCl (5 M in dioxane,
ACKNOWLEDGMENTS
6
■
We thank Dr. Antonio DiPasquale for X-ray crystallography,
Dr. Kenji Kurita for mass spectrometry, and Dr. Jerry Tso,
Brandon Scott, Keena Green, and Dr. Yanzhou Liu for
analytical support (Genentech, Inc.). We also acknowledge
Olivier Rene, Dr. Sushant Malhotra, Dr. Benjamin Fauber, Dr.
2
2
98 L, 500 mol %) was then charged into the reaction mixture
over 2 h. The mixture was stirred at 25−30 °C for 16 h, and
then the solids were collected via centrifugation and washed
with EtOAc (2 × 150 L) and heptane (4 × 150 L). The cake
F
DOI: 10.1021/acs.oprd.8b00101
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Travis Remarchuk, and Dr. Haiming Zhang (Genentech, Inc.)
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DOI: 10.1021/acs.oprd.8b00101
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(
(
on a 100 kg scale (20), possibly because of product loss during
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(
2
(
1
(
̈
3
(
EtOH, iPrOH, EtOAc, iPrOAc, MTBE, 2-MeTHF, toluene, MIBK,
acetone, and water and ∼40 mg/mL in heptane.
(
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(
19) A similar slow addition (over 30 min on a 1.0 g scale) of bicyclic
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this mode of operation was not pursued further.
(
20) For a discussion of triazole workup and purification challenges,
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H
DOI: 10.1021/acs.oprd.8b00101
Org. Process Res. Dev. XXXX, XXX, XXX−XXX