Stereoselective synthesis of monoamine reuptake inhibitor NS9544 acetate

Article abstract of DOI:10.1021/op1003117

(-)-3-(2-Benzothienyl)-8-H-8-azabicyclo[3,2,1]oct-2-ene acetate, NS9544 acetate, is a candidate drug intended to treat pain and other CNS disorders. In the synthetic route tropinone was enantioselective deprotonated with a chiral lithium amide derived from [R-(R*,R*)]-bis(α-methylbenzyl) amine hydrochloride. The formed enolate was trapped as triflate and coupled with benzo[b]thiophene-2-boronic acid under Suzuki conditions. To further enhance the enantiomeric purity crystallisation with l-(+)-tartaric acid was performed. Finally N-demethylation with trichloroethylchloroformate followed by treatment with acetic acid afforded NS9544 as the acetate salt with high enantiomeric purity.

Full text of DOI:10.1021/op1003117

ARTICLE
pubs.acs.org/OPRD
Stereoselective Synthesis of Monoamine Reuptake Inhibitor NS9544
Acetate
ꢀ
Hakan Malmgren,§ Hanna Cotton,§ Brian Frøstrup,‡ David Spencer Jones,‡ Marie-Louise Loke,‡
Dan Peters,‡,* Sara Schultz,§ Ellen S€olver,§ Tove Thomsen,‡ and Johan Wennerberg*,§
§DuPont Chemoswed, R&D, P.O. Box 839, SE-201 80 Malm€o, Sweden
‡Neurosearch A/S, Pederstrupsvej 93, DK-2750 Ballerup, Denmark
ABSTRACT: (-)-3-(2-Benzothienyl)-8-H-8-azabicyclo[3,2,1]oct-2-ene acetate, NS9544 acetate, is a candidate drug intended to
treat pain and other CNS disorders. In the synthetic route tropinone was enantioselective deprotonated with a chiral lithium amide
derived from [R-(R*,R*)]-bis(R-methylbenzyl)amine hydrochloride. The formed enolate was trapped as triflate and coupled with
benzo[b]thiophene-2-boronic acid under Suzuki conditions. To further enhance the enantiomeric purity crystallisation with L-(þ)-
tartaric acid was performed. Finally N-demethylation with trichloroethylchloroformate followed by treatment with acetic acid
afforded NS9544 as the acetate salt with high enantiomeric purity.
’ INTRODUCTION
Tropane alkaloids consists of around 200 natural products,
mostly occurring in plants of Solanaceae family.1 They all have
tropinone as the core structure, and many of them have inter-
esting pharmacological properties;1 some members are shown in
Figure 1.
Figure 1. Tropinone and members of the tropinone family.
We were interested to use tropinone as a starting material for
synthesis of a candidate drug for treatment of neuropathic pain.
NS9544 acetate (1) (Figure 2) shows an interesting pharmacolo-
gical profile as a triple monoamine reuptake inhibitor, altering the
level of activity of the monoamine neurotransmitters by the ratio of
the serotonin (5-HT), noradrenaline (NA), and dopamine (DA)
reuptake inhibition2 for the treatment of neuropathic pain.
Figure 2. NS9544 acetate, 1.
Neuropathic pain conditions involve a heterogeneous patient
population in which the underlying disease process may result in
damage to nerve transmission processes. The underlying me-
chanisms are numerous and complex, and contribute to a poor
diagnosis and treatment outcome for neuropathic pain patients.
Antidepressant drugs typically increase extracellular levels of the
catecholamine neurotransmitters serotonin, noradrenaline and/
or dopamine via inhibition of transporter function and subse-
quent block of presynaptic transmitter uptake. In this regard,
tricyclic antidepressants that act to nonselectively block the
reuptake of 5-HT and/or NA have been widely used in the
clinical treatment of neuropathic pain, albeit that they possess a
poor side-effect profile. However, selective 5-HT and NA
reuptake inhibitors such as duloxetine are devoid of many of
these side effects and can still robustly attenuate preclinical and
clinical signs and symptoms of persistent and especially neuro-
pathic pain. Compounds that can selectively modulate pain
transmission within 5-HT, NA, and DA pathways are likely to
possess a superior analgesic profile to dual mechanism of action
compounds and offer a realistic alternative to currently approved
compounds for the clinical treatment of chronic pain.3
trials. Additional methods, e.g. crystallisation, are required for
enhancing the enantiomeric excess. Despite this, asymmetric meth-
ods are preferred over resolutions where 50% of the material is
useless without further operations. In order to perform phase I
studies, access to 1 with more than 98% ee was required. We now
report a versatile protocol for the stereoselective synthesis of (-)-
3-(2-benzothienyl)-8-H-8-azabicyclo[3,2,1]oct-2-ene acetate, NS9-
544 acetate (1) at multikilogram scale.
’ RESULTS AND DISCUSSION
Initially optically pure 1 was obtained from the corresponding
racemate via chiral preparative HPLC. This methodology is
advantageous in early development since it will give access to
both enantiomers for evaluation of the pharmacological proper-
ties. However, after choosing the desired enantiomer, other met-
hods will be more expedient. Tropinone is a conformationally
restricted prochiral cyclic ketone suitable for enantioselective de-
protonation. A number of chiral lithium amide bases have been
reported to be able to discriminate between enantiotopic hydrogens
Many asymmetric methods that appear in literature give ee
values that are not accepted in drug candidates aimed for clinical
Received: November 18, 2010
Published: February 04, 2011
r
2011 American Chemical Society
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Figure 3. Chiral lithium amide base derived from [R-(R*,R*)]-bis(R-
methylbenzyl)amine hydrochloride.
Figure 4. Impurities formed during the reactions.
in such structures.4 The C2 symmetrical lithium amide 2
(Figure 3) based on [R-(R*,R*)]-bis(R-methylbenzyl)amine
was reported to work well with tropinone.5,6 This base is
commercially available for a reasonable price and can be recycled.
It is also possible to abstract different protons with different
bases.7 Majewski et al. reported that addition of one equivalent of
lithium chloride was crucial for high enantioselectivity; addition
of one equivalent of lithium chloride increased the ee from 36 to
90% in their application.6,7 The method has mainly been used for
R-functionalisation of tropinone, but in the present case we
wanted to create a carbon-carbon bond at the carbonyl carbon.
The chiral base 2 was formed by mixing one equivalent of [R-(R*,
R*)]-bis(R-methylbenzyl)amine hydrochloride with two equiva-
lents of n-butyllithium. By using the corresponding hydrochlor-
ide of the chiral amine and two equivalents of n-buthyllhium, the
chiral base and one equivalent of lithium chloride were formed in
situ. From a scale-up perspective this solution is advantageous
because the solid hydrochloride is easier to handle compared to
the free base. Free amines readily absorb carbon dioxide and
moisture from air; furthermore, they are difficult to purify. The
hydrochloride, on the other hand, is a crystalline solid which is
easy to recycle via crystallisation, and it is stable over time. In
addition the procedure ensures that dry lithium chloride is
present in the reaction.
Dry tropinone in tetrahydrofuran was added to the chiral base
in tetrahydrofuran/n-hexane at -70 °C under which the enolate
was formed. The enolate was then trapped as the triflate by adding
N-phenyl-bis-(trifluoromethanesulfonimide). The use of dry tro-
pinone was important; low enantioselectivity was achieved when
using less anhydrous tropinone. Still, without isolation a Suzuki
coupling was performed. The formed enol triflate was reacted
with benzo[b]thiophene-2-boronic acid catalysed by tetrakis-
(triphenylphosphine)palladium in the presence of tripotassium
phosphate and lithium chloride in water/tetrahydrofuran. After
2-2.5 h full conversion was verified with HPLC. Extractive
workup and treatment with n-heptane gave 3 as white crystals. In
accordance with the results from Simpkins and Majewski5-7 the
enantiomeric excess was 90%. For clinical trials such optical
purity is not sufficient and a method for enhancing the optical
purity must be developed. Conversion to a suitable salt of an
optically active acid, followed by crystallisation may be an option
to enhance the optical purity. When 3 was converted to the
corresponding tartrate salt, enantiomeric excess was raised to
98.3%. A recrystallisation from ethanol raised the optical purity
even further, and 99.2% enantiomeric excess was achieved. In
addition, byproduct 5, which was a result from homocoupling in
the Suzuki reaction, was removed in the recrystallisation. The
overall yield from tropinone to tartrate salt 4 was 63%.
it basic during the extractions. Also, the use of nonpolar solvent n-
heptane for precipitation was found important. To avoid gas
evolution, potassium carbonate, initially used in laboratory scale,
was replaced by tripotassium phosphate. During the Suzuki
coupling, byproduct 5 was formed as a result of homocoupling
of benzo[b]thiophene-2-boronic acid (Figure 4). By performing
a treatment with activated charcoal followed by hot filtration in
the recrystallisation of tartrate 4 this impurity was almost
completely removed. At this stage the assay was 97%. The
recrystallisation also had a positive effect on the palladium level
which went down from 155-215 ppm to 70 ppm.
N-Demethylation of alkaloids can be performed via a plethora
of methods.8 The first method was developed by von Braun in
the in the early 1900s.9 In the von Braun reaction the N-
methylamine is reacted with cyanogen bromide prior to cleavage
of the resulting cyanamide. The yields are low in the von Braun
reaction, and recently more efficient protocols including chlor-
oformates have been developed.10
To demethylate 4, it was converted to the free base with
sodium hydroxide. After solvent change from dichloromethane
to toluene and addition of 2,2,2-trichloroethylchloroformate,
carbamate 6 was formed. After another solvent change (at this
point to tetrahydrofuran), zinc dust and acetic acid were added.
After extractive workup and treatment with acetic acid, 1 was
obtained as the acetate. To our dismay we found that 1 was
contaminated with an impurity. The impurity was found to be 7
(Figure 4) evidenced by MS and UV spectroscopy. It was formed
because of abstraction of a chlorine atom under the reductive
reaction conditions. Impurity 7 was formed in various degrees in
the produced batches, and typically levels were 8-15%. In order
to obtain pure material, a method for purification was developed.
1 was converted to free base in toluene. This toluene solution was
dried with azeotropic distillation followed by cooling and pre-
cipitation with acetic acid. This gave a very pure material, free
from 7. However, new challenges appeared since it was not
possible to remove toluene residues to the required level.
Crystallisation from ethanol afforded 1 as acetate with high
purity in all aspects and in good yield. The assay was 100% with
only one reported impurity in 0.04%. Palladium was found to
be less than 2 ppm; lithium, less than 0.1 ppm, and zinc, about
40 ppm. During development it was noticed that ee dropped
considerably during acetate formation, and in addition yield was
low. By optimizing the concentration it was possible to raise the
yield and to minimise the loss of optical purity; ee went down
from 99.3% to 98.9% during the transformation.
’ CONCLUSION
The current approach was one out of ten evaluated. The most
obvious route would be to resolve the free base of racemic 1 with
a chiral acid, since racemic 1 is synthesised very easily. However
all attempts to resolve racemic 1 were unsuccessful. On the other
hand, it was possible to raise the enantiomeric excess in a
nonracemic mixture with classical resolution agents as described
in the presented method.
Initially the intention was to isolate 3 as hydrochloride and
perform the enhancement of the optical purity at a later stage.
This was, however unsuccessful; when the free base of 1 was
converted to tartaric acid salt or salts of other acids, sufficient
increase of ee was not obtained. In laboratory-scale development
it was found that the Suzuki coupling suffered from low yield due
to a tedious workup. It was important to control the pH and keep
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Scheme 1. Large-scale route to NS9544 acetate, 1
NS9542 Tartrate (4). In a Hastelloy reactor charged with
[R-(R*,R*)]-bis(R-methylbenzyl)amine hydrochloride (13.6 kg,
52.9 mol) and tetrahydrofuran (98 kg) was added n-butyllithium
(41.6 L, 104 mol, 2.5 M in n-hexane) under stirring at 0-10 °C
during 1 h. After stirring for an additional hour the mixture was
cooled to -80 °C, and dry tropinone11 (6.3 kg, 45.3 mol) in
tetrahydrofuran (23 L) was added during 45 min. After stirring
for 3 h, N-phenyl-bis-(trifluoromethanesulfonimide) (17.4 kg,
48.7 mol) was added during 30 min at -70 °C. After stirring for
2 h at -70 °C the mixture was allowed to warm to room
temperature overnight. The mixture was transferred to a glass-
lined reactor followed by addition of water (74 L). Benzo-
[b]thiophene-2-boronic acid (9.7 kg, 54.5 mol), tripotassium
phosphate (31.2 kg, 147 mol), and lithium chloride (2.3 kg, 54.2
mol) were added to the mixture under stirring at room tempera-
ture. The mixture was degassed by bubbling argon through the
liquid, followed by addition of tetrakis(triphenylphosphine)
palladium(0) (0.175 kg, 0.15 mol). The mixture was heated to
reflux and kept at this temperature for 2 h. The mixture was
cooled to below 30 °C, and then water (77 L), diethyl ether
(106 L), and aqueous sodium hydroxide (34 L, 2 M) were added,
followed by stirring for 10 min. After phase separation the
organic phase was transferred to another vessel. To the remain-
ing aqueous phase were added diethyl ether (34 L) and aqueous
sodium hydroxide (11 L, 2 M). After stirring for 10 min followed
by phase separation the organic phases were combined and
washed two times with aqueous sodium hydroxide (2 ꢁ 120 L,
0.4 M). Dry magnesium sulfate was added to the organic phase
followed by stirring for 2 h. The mixture was filtered and then
transferred to a stainless steel reactor. The solvent was distilled
off under reduced pressure (30f50 °C, 20 mbar) after which the
residue was cooled to -20 °C. The solidified residue was kept at
-20 °C for 1 h, then n-heptane (57 L) was added slowly. The
stirring was continued so that a suspension was formed, and after
8 h the crystals were filtered off. The crystals were washed with n-
heptane (7 L) and then charged in a glass-lined reactor. Ethanol
(139 L) was added, and the mixture was stirred for 30 min.
L-(þ)-Tartaric acid (6.8 kg, 45.3 mol) in water (13.8 L) was
added under stirring. After the crystallisation started, the mixture
was cooled to 0-5 °C and stirred at this temperature during 2 h.
The crystals were isolated via centrifugation then dried at 50 °C
under reduced pressure (20 mbar) to give 4 as white crystals.
Yield 12.75 kg, 70%.
In summary the monoamine reuptake inhibitor, NS9544
acetate (1), was prepared in essentially four steps in 22% yield
from tropinone (see Scheme 1). Chirality was introduced through
an asymmetric deprotonation of tropinone using a chiral lithium
base derived from [R-(R*,R*)]-bis(R-methylbenzyl)amine hy-
drochloride. Recrystallisation of the corresponding tartrate salt
was used to enhance the enantiomeric purity from 92% ee to 99%
ee. Two impurities were effectively removed during the se-
quence, and several steps were telescoped in order to increase
efficiency. The synthesis was performed at multikilogram scale
and gave a product of very high quality.
’ EXPERIMENTAL SECTION
General. Chiral HPLC analyses were performed using a
Chiracel OD-H, 4.6 mm ꢁ250 mm. Eluation conditions were
employed with ethanol/n-hexane (10:90). The flow rate was 0.5
mL/min and UV-detection at 290 nm. HPLC analyses were
performed using a YMC ODS-A, 5 μ, 250 ꢁ 4.6 mm, 120 Å
equipped with an SB-C18 guard PAK. Elution conditions were
employed with 20% acetonitrile in aqueous ammonium acetate
(3 mM). The flow rate was 1.0 mL/min and UV detection at
220 nm. GC analyses were performed using a J&W DB WAX,
Bodman part # 123-7033, 0.5 μm film thickness, 0.32 mm i.d.,
and 30 m length. Inlet temperature/detector temperature was
200-250 °C. Temperature gradient was 40 °C isothermal for
5 min then ramped to 200 °C at profile 50 °C/min and held at
200 °C for 10 min. Optical rotations were measured with a Perkin-
Elmer 241. NMR spectra were recorded at 300.14 MHz (proton)
and 75.47 MHz (carbon). Thin layer chromatography was per-
formed on Merck precoated TLC plates, and were visualised with
UV light or sprayed with a solution of p-methoxybenzaldehyde
(26 mL), glacial acetic acid (11 mL), concentrated sulphuric acid
(35 mL), and 95% ethanol (960 mL). Solvents and reagents were
obtained from commercial sources and were used as such without
any further purification. All reactors used are standard multipurpose
equipment, either glass-lined or stainless steel. All reactions in pilot-
plant scale are, for safety reasons, routinely carried out under an
atmosphere of nitrogen.
Recrystallisation of NS9542 Tartrate (4). In a stainless steel
reactor charged with 4 (34,4 kg, 85.5 mol) and ethanol (618 L)
was added a suspension of activated charcoal (Carboraffin P, 1.9
kg) in water (69 L) under stirring. After 15 min of stirring the
mixture was heated to reflux and kept at reflux for 15 min. The
hot mixture was filtered, and the filter was rinsed with hot ethanol
(17 L). The solution was cooled to 0-5 °C and was kept at this
temperature for at least 2 h. The crystals were isolated via
centrifugation, then dried at 50 °C under reduced pressure (20
mbar). The yield of the title compound was 31.1 kg (90%) with
an ee of 99.3%. [R]23D = þ24.5 (c = 1.6, EtOH.); IR 3052 broad,
1717, 1591, 1125, 1069 cm-1; 1H NMR (CDCl3) δ 7.79-7.71
(m, 2H), 7.37-7.33 (m, 2H), 7.22 (s, 1H), 6.29 (d, J = 5.4 Hz, 1
H), 4.22 (s, 2H), 4.19-4.08 (m, 2 H), 3.29-3.10 (m, 1 H), 2.87
(s, 3 H), 2.64 (d, J = 19.0 Hz, 1 H), 2.63-2.46 (m, 2 H), 2.32-
2.23 (m, 1 H), 2.02-1.89 (m, 1 H); HRMS calcd for C20H19-
NO6S (M þ H) 242.1003, found 242.1002.
NS9544 Acetate or (-)-3-(2-Benzothienyl)-8-H-8-azabicy-
clo[3,2,1]oct-2-ene Acetate (1). In a stainless steel reactor
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charged with 4 (31.0 kg, 77.1 mol) dissolved in water (310 L)
were added dichloromethane (310 L) and aqueous sodium
hydroxide (81 L, 2 M, 162 mol) under stirring. The mixture
was stirred for 10 min after which the phases were allowed to
separate. The organic phase was transferred to another vessel and
the remaining aqueous phase was extracted with dichloromethane
(86 L) followed by a combination of the organic phases. The
combined organic phases were then washed with water (258 L)
and dried over magnesium sulfate (13 kg). After filtration the
solvent was distilled off under reduced pressure (20 mbar) at
45 °C. Toluene (256 L) was added under stirring. To dry the
solution and eliminate residues of dichloromethane 35 L of
toluene was distilled off under atmospheric pressure. The
mixture was cooled to 20-25 °C after which 2,2,2-trichlor-
oethyl chloroformate (21.3 kg, 100.5 mol) was added under
stirring. After at least 10 h with stirring at room temperature,
water (172 L) was added, and stirring was continued for 1 h.
Diethyl ether (327 L) was added followed by stirring for 15 min.
The organic phase was separated and washed with water (2 ꢁ
86 L). Five hundred and fifty liters of solvent were distilled off
under reduced pressure (20 mbar) with the jacket temperature
set to 60 °C. To the residue was added tetrahydrofuran (172 L),
and the mixture was stirred for 15 min. Under stirring was added
acetic acid (37 L) and water (65 L) followed by addition of zinc
dust (8.7 kg, 133 mol) in 10 portions during 1 h (CAUTION!
Exothermic, evolution of carbon dioxide; risk for foaming!). The
temperature of the reactor was kept below 50 °C during the
addition. After cooling to 20 °C the mixture was stirred for 10 h.
To eliminate residues of zinc, the mixture was transferred to
another reactor via a cartridge filter. Aqueous hydrochloric acid
(28 L, 4 M) was added to the reaction mixture under stirring.
Then 200 L of tetrahydrofuran was distilled off under reduced
pressure (20 mbar); meanwhile, the precipitation started. The
mixture was cooled to 0-5 °C and stirred at this temperature for
at least 90 min. The precipitate was isolated on a filter and
washed with water (2 ꢁ 45 L) and diethyl ether (2 ꢁ 45 L). The
wet filter cake was charged to a glass-lined reactor after which
water (172 L), dichloromethane (172 L), and aqueous sodium
hydroxide (100 L, 2 M) were added. The mixture was heated to
reflux and kept at reflux for 10 min; after cooling to 20 °C the
phases were allowed to separate. The organic phase was trans-
ferred to another reactor, and the aqueous phase was extracted
with dichloromethane (86 L). After separation, the organic
phases were combined and dried over magnesium sulfate (13 kg).
After filtration the mixture was concentrated to approximately
20 L under reduced pressure (20 mbar) at 45 °C in a reactor.
The final concentration was performed in a 50-L evaporator
under the same conditions. Rapidly, before solidification started,
the warm oil was transferred to a reactor. To the oil was added
ethanol (63 L), and the mixture was heated to reflux. After 30 min
at reflux, acetic acid (3.63 L, 75.6 mol) was added, and the
mixture was cooled to 20-25 °C during 30 min. Diethyl ether
(56 L) was added and the mixture was cooled to 0-5 °C, then
left for at least 3 h. The precipitated product was collected on
a filter and washed with cold ethanol (8.2 L) and diethyl ether
(10.8 L). Drying of the product at reduced pressure (20 mbar) at
60 °C for 10 h gave 10.9 kg (47%) of the title compound as white
crystals.
heated to reflux and kept at reflux for 30 min. After cooling to
20-25 °C the phases were separated, and the organic phase
was washed with water (77 kg). The solution was filtered
trough a 0.5 μm polish filter to another reactor. The mixture
was dried by azeotropic distillation until no more water was
separated. A solution of acetic acid (2.4 kg, 40 mol) in toluene
(10 kg) was added at 100 °C. The mixture was cooled to 20-
25 °C which initiated crystallisation; stirring was continued
overnight. Isolation was performed with centrifugation; the
filter cake was washed with ether (7 kg), followed by drying at
reduced pressure at 40 °C and 20 mbar. The dry material was
charged in a reactor together with ethanol (36 kg) and heated
to reflux. Acetic acid (0.18 kg, 3 mol) was added, after which
crystallisation was induced by cooling. At room temperature,
diethylether (32 kg) was added, and the mixture was kept at 0-
5 °C overnight. The product was isolated via filtration and
dried at 50 °C and 20 mbar to give the title compound as white
crystals in 9.0 kg (83%) yield, ee 98.9%, mp 182-183 °C
(lit.177 °C);2 [R]23 = -15.1 (c = 2.2, EtOH.); IR 2937
D
(broad), 1719, 1552, 1393 cm-1; 1H NMR (CDCl3) δ 7.76-
7.64 (m, 2H), 7.32-7.26 (m, 2H), 7.12 (s, 1H), 6.42 (d, J = 5.7
Hz, 1 H), 4.18-4.08 (m, 2H), 3.21 (dd, J1 = 17.2 Hz, J2 = 4.9
Hz, 1H), 2.43 (d, J = 17.2 Hz, 1H), 2.34-2.19 (m, 1H), 2.11
(dd, J1 = 8.1 Hz, J2 = 3.6 Hz, 1H), 1.86 (s, 3H), 1.82-1.71
(m, 1H); 13C NMR (CDCl3) δ 177.3, 143.2, 139.7, 138.2,
128.3, 127.2, 124.5, 124.1, 123.2, 121.8, 119.4, 52.7, 51.8, 35.9,
33.4, 28.5, 22.7; Anal. Calcd for C17H19NO2S: C, 67.7, H, 6.3,
N, 4.6; Found C, 67.5, H, 6.4, N, 4.6.
’ AUTHOR INFORMATION
Corresponding Author
*Telephone þ46-40-383316. Fax þ46-40-186805. E-mail:
johan.wennerberg@swe.dupont.com.
’ ACKNOWLEDGMENT
We are grateful to Hans Uvelius, Johnny Dahl and Lars L€ofvall
for running the pilot plant and to Ola Olsson for analytical
assistance.
’ REFERENCES
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Purification of NS9544 Acetate (1). In a reactor charged
with toluene (66 kg) was added 1 (10.88 kg, 36.12 mol) under
stirring. To the resulting solution were added water (77 kg)
and aqueous sodium hydroxide (22 kg, 2 M). The mixture was
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(11) In a glass-lined reactor tropinone (19.3 kg) was dissolved in
diethyl ether (43 kg). Magnesium sulfate (1.2 kg) was added, and the
mixture was stirred for 3 h. The mixture was filtered through a bag filter
followed by filtering through a cartridge filter. The reactor and filter were
washed with diethyl ether (11 kg). The combined organic solutions were
evaporated to dryness in a Buchi Rotavapor R-250. Yield 18.4 kg
(95.3%).
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