Process research for multikilogram production of etamicastat: A novel dopamine β-hydroxylase inhibitor

Article abstract of DOI:10.1021/op300012d

In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evoluti

Full text of DOI:10.1021/op300012d

Lecture Transcript
pubs.acs.org/OPRD
Process Research for Multikilogram Production of Etamicastat: A
Novel Dopamine β-Hydroxylase Inhibitor
Alexandre Beliaev,* Jorge Wahnon, and Domenico Russo
Laboratory of Chemistry, Department of Research and Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal
ABSTRACT: In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-
aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione
fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of
readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about
significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric
hydrogenation.
a
Scheme 1. Medchem route to amine 2
INTRODUCTION
■
Etamicastat (BIA 5-453 or (R)-5-(2-aminoethyl)-1-(6,8-difluor-
ochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride,
1) (Chart 1) is a novel peripherally selective dopamine β-
Chart 1
hydroxylase (DBH) inhibitor being developed by Bial-Portela
and Ca, S.A. for treatment of hypertension and congestive heart
failure.1 The compound was shown to be well tolerated in
healthy volunteers.2
An important part of etamicastat structure is (R)-3-amino-
6,8-difluorochroman (2) (Chart 1) which is also an
intermediate in all known syntheses of the drug. In the original
medicinal chemistry route,3 the amine 2 was synthesized
starting from L-serine methyl ester hydrochloride (3) by
condensation of its N-trityl derivative (4) with 2,4-difluor-
ophenol under Mitsunobu conditions,4 followed by depro-
tection of the adduct (5), ethoxycarbonylation of the resulting
amino acid (6), Friedel−Crafts cyclization5 of N-protected
derivative (7) and reduction6 of the ethoxycarbonylamino
ketone (8). The alkaline hydrolysis of ethyl carbamate (9) gave
amine 2, which was isolated as the hydrochloride salt (Scheme
1).
a
Reagents and conditions: a) Trt-Cl, Et3N, DMF, rt, 16 h; b) 2,4-
difluorophenol, Ph3P, DEAD, benzene, rt, 2 h; c) 1.4 N HCl in EtOAc,
rt, 1 h; d) 1 N NaOH, MeOH, rt, 4 h; e) ethyl chloroformate, NaOH,
water, 0−5 °C, 1 h; f) PCl5, DCM, 0−5 °C, 1 h; g) AlCl3, DCM, 3−8
°C, 4 h; h) 100 psi H2, Pearlman’s catalyst, H2SO4, CF3COOH, rt, 24
h; i) 40% KOH, MeOH, reflux, 24 h; j) 2-propanol, conc HCl, rt.
To form the 5-(2-aminoethyl)-1,3-dihydroimidazole-2-thione
moiety in the original route, the tert-butyl 4-(tert-butyldime-
thylsilyloxy)-3-oxobutylcarbamate (13) building block was
prepared starting from the known amino diol (10),7 and then
reacted with amine 2 and potassium thiocyanate in ethyl acetate
in the presence of acetic acid. Under the conditions employed
for cleavage of the Boc group (1 N HCl/EtOAc) in the
resulting hexahydropyrrolo[2,3-d]imidazole-2-thione derivative
14, simultaneous opening of the pyrrolidine ring occurred to
give the target compound 1 (Scheme 2).
Part of the medicinal chemistry route (including preparation
of intermediates 2 and 13), and the cyclocondensation reaction
suffer from various technological drawbacks, which make the
process less convenient for scale-up. For example, intermediates
5 and 12−14 are noncrystalline and require chromatographic
purification, the reaction medium used for reduction of ketone
Received: January 16, 2012
Published: March 1, 2012
© 2012 American Chemical Society
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a
volume of methanesulfonic acid gave complete conversion of 8
to 9. However, the analysis of the optical purity of compound 9
revealed significant racemization. The racemization was
attributed to the enantiomeric instability of the starting
compound 8 in the reaction mixture. To overcome the
racemization issue, a two-step method, comprising the
conversion of 8 to the intermediate alcohol with sodium
borohydride in methanol followed by catalytic reduction in the
dichloromethane−methanesulfonic acid mixture, was inves-
tigated. At laboratory scale, the two-step process reproducibly
gave high yield of compound 9 with 94−99% ee. This was
successfully demonstrated in the first kilo batches at 5-kg scale.
It was then decided to produce the first pilot batches, and when
the reaction was carried out on 100-kg scale, some racemization
was noticed both for the Friedel−Crafts cyclization and
reduction steps. Compound 9 was obtained with unexpectedly
lower enantioselectivity of 80% ee. Isolation of compound 2 as
the L-tartrate salt upgraded the optical purity to the required
98% ee. An overview of the L-serine route to compound 2 that
was taken to the pilot scale is depicted in Scheme 315
Scheme 2. Medchem synthesis of etamicastat
a
Reagents and conditions: a) Boc2O, EtOH, rt, 2 h; b) TBDMS-Cl,
Et3N, DMAP, DCM, rt, 18 h; c) Dess−Martin periodinane, DCM, rt,
Scheme 3. Optimized L-serine route to (R)-3-amino-6,8-
difluorochroman (2)
a
1 h; d) 2, KSCN, AcOH, EtOAc, reflux, 7 h; e) 2 N HCl, EtOAc, rt, 2
h.
8 (mixture of trifluoroacetic and sulfuric acids6) is very
corrosive, and the yield obtained in this step is low. It was
therefore necessary to optimize the existing scheme or develop
an alternative approach to prepare kilogram quantities of
etamicastat to supply clinical trials.
DEVELOPMENT OF SYNTHETIC ROUTES TO
(R)-3-AMINO-6,8-DIFLUOROCHROMAN (2)
■
Initial efforts were directed to optimization of the route
depicted in Scheme 1. Preparation of the difluorochroman 2
was lengthy, and several unit operations were required. After
some familiarization with the process, it was found that
isolation of N-trityl derivative (4) was not necessary if the
tritylation solvent was changed from DMF to dichloromethane.
Telescoping to amino acid 6 was successfully achieved by
avoiding chromatographic purification of the Mitsunobu
reaction and directly performing a biphasic hydrolysis of the
reaction mixture followed by isolation of the amino acid 6 from
the aqueous layer after neutralization. N-Protected amino acid
(7) could also be telescoped to the Friedel−Crafts cyclization
step in DCM solution without isolation. One difficult task
appeared to be optimization of reduction of the ketone 8.
Reduction of aryl ketones (such as compound 8) to methylene
compounds (such as compound 9) is a synthetically useful
reaction, and various methods have been developed for this
transformation, namely Clemmensen and Wolff−Kishner
reductions, catalytic hydrogenolysis,8−10 Et3SiH/
CF3COOH,9,10 Et3SiH/BF3·Et2O,10 Et3SiH/TiCl4,11 NaBH4/
BF3·Et2O.12 However, in our experiments none of the above
methods proved to be efficient for the conversion of 8 to 9,
yielding the intermediate alcohol or its mixture with the starting
material. Attempts to reduce the intermediate alcohol to 9 with
other reagents known to be efficient for this kind of
transformation, such as iodotrimethylsilane13 or its equiv-
alents14 did not work either. A screening of different solvent−
acid combinations for catalytic hydrogenolysis over Pd/C was
performed, and surprisingly, it was found that carrying out the
reduction in a mixture of 3 volumes of dichloromethane and 1
a
Reagents and conditions: a) Trt-Cl, Et3N, DCM, rt, 6 h; b) 2,4-
difluorophenol, Ph3P, DIAD, toluene, 25−30 °C, 4 h; c) 6 N HCl,
reflux, 1 h; d) 32% NaOH, water, rt; e) ethyl chloroformate, NaOH,
water, 0−5 °C, 1 h; f) PCl5, DCM, 0−5 °C, 3 h; g) AlCl3, DCM, 3−8
°C, 6 h; h) NaBH4, MeOH, 5−10 °C, 30 min; i) 100 psi H2, 10% Pd/
C, MSA, DCM, rt, 7 h; j) 40% KOH, MeOH, reflux, 24 h; k) L-tartaric
acid, ethanol, water, rt, 1 h.
Although the optimized L-serine route allowed the
preparation of multikilogram quantities of compound 2, due
to the relatively high cost of starting materials, moderate yields,
and more importantly, configurational instability of the
protected amino ketone 8 on scale, the process required
further optimization for commercial production.
After the L-serine route, another alternative synthethic
pathway, employing asymmetric hydrogenation of a corre-
sponding ene-carbamate as a chiral center-forming step, was
developed. Ene-carbamates 19 were prepared on laboratory
scale starting from 2,4-difluorophenol 15 by formylation with
hexamethylenetetramine in trifluoroacetic acid to aldehyde 16,
and subsequent cyclization with acrylonitrile in the presence of
DABCO to afford nitrile 17. Alkaline hydrolysis of 17, followed
by the Curtius rearrangement of the corresponding acyl azide in
the appropriate alcohol or alcohol−toluene mixture, gave the
requisite ene-carbamates 19 (Scheme 4).16 For asymmetric
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a
Scheme 4. Synthesis of carbamates 20 via Curtius reaction
Scheme 5. Optimized route to (R)-3-amino-6,8-
difluorochroman (2) via asymmetric reduction of ene-
a
carbamate 22
a
Reagents and conditions: a) HMTA, CF3COOH, 115 °C, 18 h; b)
CH2CHCN, DABCO, DMF, water, 70 °C, 16 h; c) H2SO4, AcOH,
100 °C, 1 h; d) NaClO, NaOH, MeOH, 25 °C, 24 h; e) Ru
biphosphine catalyst S/C 4000, 30 bar H2, MeOH, 80 °C, 20 h; f)
water, 2-propanol, reflux to 20 °C; g) 40% KOH, MeOH, reflux, 24 h;
h) L-tartaric acid, ethanol, water, rt, 1 h.
a
Reagents and conditions: a) HMTA, CF3COOH, 115 °C, 18 h; b)
CH2CHCN, DABCO, reflux, 16 h; c) NaOH, water, reflux, 4 h; d)
DPPA, Et3N, acetone, 15 °C, 2 h; e) ROH or ROH−toluene, 60−100
°C, 3−5 h; f) Ru biphosphine catalyst S/C 100, 30 bar H2, MeOH, 60
°C, 20 h.
similar to that of the cleavage of ethyl carbamate 9, resulting in
the amine 2 with 99% ee (Scheme 5).
After performing the first kilo batches (5-kg scale), the
process was considered suitable for further scale-up. Several
100-kg scale batches of the amine 2 L-tartrate were produced,
yielding product that was within chemical and optical purity
specifications. From the point to view of waste generation, the
optimization work carried out in the ene-carbamate route led to
a significant reduction in waste. The reduction was about 20%
when compared to optimized L-serine route.
Although the process was shown to be scalable and robust,
alternative routes to ene-carbamate 22 were evaluated at the
same time in order to further increase cost efficiency of the
method. One of the strategies focused on an intramolecular
version of Pd-catalyzed α-arylation of aliphatic ketones,21 which
was expected to produce 3-chromanone 26 from methyl ketone
25 (Scheme 6). Bromination of 2,4-difluorophenol (15)
proceeded smoothly, as described,22 to give bromo phenol
24, and alkylation of the latter with chloroacetone produced
ketone 25 in high yield. Unfortunately, cyclization of 25 to 26
hydrogenation of 19, the catalyst screening program was
initially performed with a S/C ratio 100 using a preformed Ru
or Rh catalyst in methanol at 30 bar H2 and at 60 °C for 20 h.
Conversion and ee were followed by chiral HPLC. The best
hydrogenation results (full conversion at 90−95% ee) were
obtained with methyl carbamate (19, R = Me) in conjunction
with Ru complexes of (R)-Xyl-P-Phos,17 CatASium T3,18 (R)-
C3-TunePhos19 and (R)-TolBINAP20 ligands. Early studies
showed that the presence of phosphoric acid was beneficial to
the reaction with respect to conversion and ee.
After completion of the asymmetric hydrogenation proof of
concept, further optimization of both the ene-carbamate
substrate preparation method and the reduction step was
undertaken. It was found that the presence of water was not
detrimental for the cyclocondensation of aldehyde 16 and
acrylonitrile which allowed taking the water-wet cake of 16 to
the next step, thus avoiding drying of the volatile product
(Scheme 5). The acrylonitrile (suspected carcinogen) that was
used in high quantities as a reagent and solvent was largely
replaced by a DMF−water mixture, thus minimizing the safety
risk and facilitating isolation of the nitrile 17 (by crystallization
upon cooling). As the use of azide chemistry may be
undesirable at scale, a modified procedure that allowed a
safer method and was more amenable to larger-scale
production was investigated. A suitable alternative procedure
was devised using the Hofmann rearrangement of carboxamide
(21) (which was prepared by the acidic hydrolysis of nitrile
(17)16) affording the methyl ene-carbamate (22) in com-
parable yield. An exhaustive optimization of conditions for the
asymmetric reduction of ene-carbamate 22 allowed the S/C
ratio to be increased to 4000:1 without loss of enantioselectivity
or conversion. Recrystallization of crude carbamate (23, 92%
ee) from aqueous 2-propanol efficiently removed unwanted
enantiomer, affording 23 with 98% ee in high yield. Alkaline
hydrolysis of methyl carbamate 23 was performed in a way
Scheme 6. Route to ene-carbamate 22 via intramolecular α-
a
arylation of aliphatic ketone
a
Reagents and conditions: a) Br2, water, 0−5 °C, 2 h; b)
chloroacetone, K2CO3, cat. KI, THF, reflux, 4 h; c) Pd complex,
base, heating in organic solvent; d) CuI, DMEDA, base, heating in
organic solvent.
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did not achieve the yield required to make this interesting for
further development.
Scheme 8. Synthesis of 1 via malonate addition to
hydroxymethylimidazole 29
a
Another approach was based on the Cu-catalyzed ring
closure of aromatic bromides with 1,3-dicarbonyl moiety24
which implies the replacement of chloroacetone in Scheme 6
with commercially available and relatively cheap ethyl 4-
chloroacetoacetate (Scheme 7). Alkylation of phenol 24 was
Scheme 7. Route to ene-carbamate 22 via intramolecular α-
a
arylation of 1,3-dicarbonyl derivative
a
Reagents and conditions: a) dihydroxyacetone dimer, KSCN, AcOH,
EtOAc, 50 °C, 2 h; b) diethyl malonate, EtONa, EtOH, 20−25 °C, 16
h; c) NaOH, water, MeOH, 20−25 °C, 4 h; d) HCOOH, Et3N, 115
°C, 2 h; e) DPPA, Et3N, EtOAc, 0−5 °C, 4.5 h; f) 1N HCl, HCOOH,
dioxane, 60−75 °C, 1.5 h.
the corresponding diester (not shown). After hydrolysis and
decarboxylation this gave imidazolepropionic acid 30 in high
yield.26 Conversion of the acid 30 to 1 was achieved via a two-
step Curtius process involving isolation of the intermediate acyl
azide to give an overall yield of 40−45%. All attempts to
perform the reaction without isolation of the azide or to use
alternative azide-free processes (Hofmann or Schmidt reac-
tions) were unsuccessful.
A subsequent development of the above approach was an
attempt to use a malonate analogue with the amino group
incorporated in the correct position for the reaction with 29.
Among several tested glycine derivatives, condensation with the
benzophenone imine 31 in THF in the presence of potassium
tert-butoxide was successful (Scheme 9). The primary adduct
32 was fully deprotected without isolation to give crystalline
amino acid 33 as a mixture of diastereomers in moderate yield.
Decarboxylation of 33 occurred in refluxing cyclohexanol (156
°C) although 2-cyclohexen-1-one was required as a catalyst.27
Due to harsh conditions, the reaction was accompanied by
a
Reagents and conditions: a) ethyl 4-chloroacetoacetate, KOH,
DMSO, 20−25 °C, 1.5 h; b) CuI, DMEDA, K2CO3, dioxane, reflux,
6.5 h; c) 20% aqueous H2SO4, reflux, 16 h; d) N-methyl carbamate, p-
TsOH, toluene, reflux, 1 h.
carried out in DMSO solution in the presence of potassium
hydroxide. After chromatographic purification this yielded the
adduct 27 as an oil in a moderate yield. The cyclization
performed sluggishly, producing the enol form of chromanone
28 in low yield after column chromatography, although the
crude reaction mixture contained approximately 80% of the
desired product. Hydrolysis of the ester group followed by
decarboxylation was performed without isolation of the
intermediate acid by refluxing compound 28 in 20% sulfuric
acid to give ketone 26. Conversion of the latter to the target
ene-carbamate 22 was achieved according to the published
procedure,24 with >80% yield (crude compound). However,
due to formation of many impurities, chromatographic
purification became necessary, and the isolated yield was
therefore low. However, a direct crystallization from acetic
acid/water is sufficient to avoid the chromatography step.
The chemistry depicted in Scheme 7 is feasible and attractive
from the cost-of-goods perspective. However, due to low
isolated yields seen in several steps, the need for chromato-
graphic purification and noncrystalline intermediate 27, route
optimization is to be considered for Scheme 7.
Scheme 9. Synthesis of 1 via glycinate addition to
a
hydroxymethylimidazole 29
DEVELOPMENT OF SYNTHETIC ROUTES TO
ETAMICASTAT
■
As has already been mentioned, all studied synthetic routes to
etamicastat employed (R)-3-amino-6,8-difluorochroman (2) as
starting material. Initially, the medchem route did not seem
convenient for development as all the intermediates were oils.
The first tested approach consisted of reacting hydroxymethy-
limidazole with a C nucleophile via direct displacement of the
hydroxy group. Hydroxymethylimidazoles have been shown to
react with N-nucleophiles.6,25 The hydroxymethyl intermediate
29 was prepared by cyclocondensation of 2 with a
dihydroxyacetone dimer and potassium thiocyanate in ethyl
acetate in the presence of acetic acid (Scheme 8).
a
Reagents and conditions: a) t-BuOK, THF, −5−0 °C to 20−25 °C, 3
h; b) LiOH, THF, water, 20−25 °C, 16 h; c) AcOH, distillation of
THF and water; d) 2-cyclohexen-1-one, cyclohexanol, reflux, 2 h.
We have found that in the presence of sodium ethoxide,
diethyl malonate reacted cleanly with compound 29, affording
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a
some decomposition, and isolation of the product required
chromatographic purification. Compound 1 was produced in
moderate yield.
Scheme 11. Large-scale route to etamicastat 1
Yet another tested approach towards the construction of
imidazolethione moiety is shown in Scheme 10. Dimethoxy
a
Scheme 10. Route to 1 via protected α-amino aldehyde 37
a
Reagents and conditions: a) methyl vinyl ketone, t-BuONa, EtOAc,
EtOH, 40−50 °C, 2−3 h; b) Br2, MeOH, 20−25 °C, 5 h; c) water,
reflux, 1 h; d) KOH, AcOH, reflux, 1 h; e) HCl, water, 2-propanol, 75
°C, 4 h; f) compound 2 L-tartrate, KSCN, AcOH, 100 °C, 2−4 h; g)
recryst. from 2-propanol/DCM; h) NaBH4, 2-propanol, DCM, water,
20−25 °C, 16 h; i) HCl, 2-propanol, water, reflux, 1−2 h.
bromine during 8 h which allowed a controlled heat release.
Compound 43 is a stable crystalline material which can be
recrystallized from 2-propanol. The above chemical route
allowed for its preparation in good yield with 99% purity.
Cyclocondensation of ketone 43 with the L-tartate of amine 2
and potassium thiocyanate was performed in acetic acid at 100
°C. The target imidazolethione 44 cocrystallized with
potassium tartrate upon dilution of the reaction mixture with
water and cooling. The tartrate salt was then removed by
recrystallization from 2-propanol−DCM. Because of a moder-
ate yield on the cyclization step, an extensive optimization work
was performed. However, neither alteration of the ratio of
reagents nor fine-tuning of the reaction parameters increased
the yield. Removal of the phthalyl-protecting group was
performed using a modified sodium borohydride method30
and produced 1 in high yield and also purity above 99%. A
critical parameter in this step was the hydrogen formation and
accumulation during the reaction. To avoid the risk of
hydrogen accumulation on scale, the addition of sodium
borohydride was carried out in steps during a period of 4 h (10-
min intervals) whilst maintaining the temperature below 10 °C.
By combining the route in Scheme 11 with the process of
amine 2 synthesis (depicted in Scheme 5), the convergent 12-
step process was used for industrial scale production of
etamicastat (1). Three lots of approximately 60 kg each were
produced with overall yield 11% starting from difluorophenol,
and the product complied with the defined specifications.
a
Reagents and conditions: a) 1,1-dimethoxyacetone, HCHO, HCl,
water, reflux, 4 h; b) ethyl chloroformate, Et3N, MeOH, 20−25 °C, 2
h; c) compound 2, STAB-H, DCM, 20−25 °C, 4 h; d) KSCN, 1 N
HCl, EtOH, reflux, 5 h.
ketone 36 was used as a model substrate for reductive
alkylation of amine 2 to produce protected α-amino aldehyde
37. Cyclocondensation of the latter with potassium thiocyanate
afforded the desired imidazolethione 38 in reasonable yield.
However, the route was not further developed as no convenient
synthetic method for N-protected 4-amino-1,1-dimethoxybu-
tan-2-one was available. For example, ketone 36 was prepared
by Mannich reaction of benzylamine (34) followed by
ethoxycarbonylation of intermediate 35 of an overall yield of
only 5%.
Finally, the medchem route (Scheme 2) was reassessed in
order to find suitably protected 4-amino-1-hydroxybutan-2-one
(analogue of ketone 13) to be used in the cyclocondensation
reaction with amine 2 and thiocyanate. To be amenable to
larger-scale preparation, the intermediate needs to be readily
available, crystalline, and able to give cyclization product that
crystallizes easily. After an extensive study of various protecting
groups, the phthalimido hydroxy ketone 43 was selected
(Scheme 11).28
The hydroxy ketone 43 was prepared using standard
chemistry by Michael addition of methyl vinyl ketone to
phthalimide (39), selective bromination of ketone 40 in
methanol,29 conversion of bromide 41 to acetoxy derivative
42 and finally acidic hydrolysis of the latter. The bromination
reaction of compound 40 was assessed with other reagents to
avoid the use of bromine due to its toxic properties. Reagents
such as N-bromosuccinimide or 5,5-dimethyl-1,3-dibromohy-
dantoin failed to generate the desired product. Calorimetric
studies on the bromination reaction were carried out (RC1 and
DSC), and it was found that ΔT (adiabatic) is 22 °C. A second
exotherm was also observed because of product crystallization
during reaction. This was overcome on scale by charging
CONCLUSION
■
A convergent manufacturing route to etamicastat (1) has been
developed and scaled up to 60 kg batches. Several synthetic
approaches to the pivotal chiral 3-aminochroman intermediate
(2) were studied using both starting material from the chiral
pool and by constructing the chiral center via asymmetric
hydrogenation. Several methods for building 2-aminoethyl
imidazolethione fragment were tested. The manufacturing
route utilizes readily available inexpensive starting materials.
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Lecture Transcript
(20) Beliaev, A.; Learmonth, D. A. Process. PCT Int. Appl. WO/
2009/136803A2, 2009.
AUTHOR INFORMATION
■
Corresponding Author
*Telephone: 351-22-9866100. Fax: 351-22-9866192. E-mail:
alexander.beliaev@bial.com.
(21) Muratake, H.; Natsume, M. Palladium-catalyzed intramolecular
α-arylation of aliphatic ketones. Tetrahedron Lett. 1997, 38, 7581.
(22) Finger, G. C.; Gortatowski, M. J.; Shiley, R. H.; White, R. H.
Aromatic Fluorine Compounds. VIII. Plant Growth Regulators and
Intermediates. J. Am. Chem. Soc. 1959, 81, 94.
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(25) Macor, J. E.; Cornelius, L. A. M.; Roberge, J. Y. Direct
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(26) Soares-da-Silva, P.; Beliaev, A.; Learmonth, D. A. Process for the
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(28) Soares-da-Silva, P.; Beliaev, A.; Learmonth, D. A. Process for the
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Notes
The authors declare no competing financial interest.
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