Op034094j Si 001
Op034094j Si 001
Op034094j Si 001
Microlab. The actual charges of substrates and reagents are given below. The molar
amounts are calculated based on the assays of the materials. Similarly, yields are
calculated based on assay corrected moles of substrates and products. Proton (1H)
nuclear magnetic resonance (NMR) spectra were recorded on either a Unity Inova Varian
1
300 MHz or Unity Inova Varian 400 MHz spectrometer. H NMR descriptions are
Carbon (13C) nuclear magnetic resonance (NMR) spectra were recorded on either a Unity
Inova Varian 300 or Unity Inova Varian 400 spectrometer at 75 MHz and 100 MHz,
respectively.
EM Science 0.25 nm Silica Gel 60, glass-backed plates with F254 indicator. UV light was
0-63 mesh Silica Gel. Liquid chromatography and mass spectrum analysis were
performed on an Agilent 1100 Series LC/MSD model number G1946D equipped with an
APCI ionization source and photodiiode array. Chiral HPLC method for separation of
TEA as eluting solvent at a flow rate of 1mL/min monitored at 254 nm. The (S)-isomer:
retention time was 7.6 min. and the (R)-isomer was 8.4 min.
For pilot plant operations, operators generally employed standard safety precautions
including the use of a full-face respirator when charging all materials. Operators were
fitted with either a Tyvek suit or smock and chemical resistant gloves when charging
highly hazardous materials. Special equipment needs are noted in the experimental
description. All equipment was cleaned and dried to specification prior to use.
1,1-Dimethylethyl (E)-3-[3-bromo-5-chloro-2-(methoxymethoxy)phenyl]-2-
propenoate (6). To a rapidly stirred suspension of anhydrous LiCl (1.6 g, 0.038 mol) in
anhydrous acetonitrile (308 mL) under nitrogen at room temperature was added t-butyl
diazabicyclo[5.4.0]undec-7-ene (DBU) (5.04 g, 5.0 mL, 0.033 mol) and 5 (8.8 g, 0.031
mol). The mixture was stirred until complete by TLC (typically 2-3 hours) by which time
all of the lithium salt had dissolved. The mixture was then poured into water (200 mL)
and the product removed by filtration. The solid was washed with water (4 x 50 mL) then
dissolved in ethyl acetate (200 mL). The ethyl acetate solution was washed with brine (50
mL), dried (MgSO4), filtered and concentrated. The product was an off-white solid (9.7 g,
82%): mp. 83.0 C; IR (nujol mull) 1713, 1294, 1276, 1255, 1221, 1161, 1042, 994, 960,
914, 880, 863, 754, 721, 697 cm-1; 1H NMR (CDCl3) 7.87 (d, 1H, J = 16.5 Hz, trans
alkene CH), 7.59 (d, 1H, ArH), 7.51 (d, 1H, ArH), 7.36 (d, 1H, J = 16.5 Hz, trans alkene
CH), 5.00 (s, 2H, CH2), 3.61 (s, 3H, CH3), 1.47 (s, 9H, tBu); 13C (CDCl3) 165.8 (CO),
152.6 (C), 137.2 (CH), 134.3 (CH), 132.4 (C), 130.9 (C), 126.5 (CH), 123.8 (CH), 119.1
(2.24 g, 0.056 mol) in water (60 mL) cooled to 0-5 C was added in aliquots (S)-N-allyl-
-methylbenzylamine hydrochloride (10 g, 0.051 mol) while maintaining the temperature
between 0-5 C. The mixture was stirred for 10 min. then extracted with TBME (3 x 20
mL). The combined extracts were washed with brine, dried (MgSO4), filtered and
concentrated. The amine was isolated as a pale yellow oil (7.0 g, 86%): 1H NMR (CDCl3)
7.25-7.11 (m, 5H, ArH), 5.81 (m, 1H, Allyl CH), 5.05 (m, 2H, Allyl CH2), 3.72 (q, 1H,
CH), 3.00 (d, 2H, Allyl NCH2), 1.29 (d, 3H, CH3).
1,1-Dimethylethyl (3R)-3-{allyl[(1S)-1-phenylethyl]amino}-3-[3-bromo-5-chloro-
methylbenzylamine (469 mg, 2.91 mmol) in anhydrous THF (9.6 mL) at 0-5 C was
added dropwise n-butyllithium (1.6M hexanes solution, 1.82 mL, 2.91 mmol). The
solution was stirred for 30 min. then cooled to 30 C. A solution of 6 (1.0 g, 2.649
mmol) in anhydrous THF (2.5 mL) was then added dropwise and the reaction stirred at
30 C for 2 hours. Saturated NH4Cl solution (2 mL) was added and the mixture diluted
with TBME (10 mL). The aqueous phase was extracted with TBME (3 x 2 mL) and the
combined organics washed with 1M citric acid (3 x 5 mL), saturated NaCO3 (2 x 5 mL)
and brine (5 mL). The organic phase was dried (MgSO4), filtered and concentrated. The
residue was purified on silica gel eluting with 0-5 % ethyl acetate/hexane. The product
was obtained as a colorless oil (1.06 g, 75%): IR (thin film) 3077, 2977, 2931, 1727,
1450, 1433, 1392, 1368, 1297, 1250, 1203, 1158, 1076, 946, 760, 700 cm-1; 1H NMR
(CDCl3) 7.33-7.05 (m, 7H, ArH), 5.71 (m, 1H, allyl CH), 5.12-4.85 (m, 4H, allyl CH2
and MOM CH2), 4.81 (dd, 1H, NCH), 3.97 (q, 1H, NCHCH3), 3.51 (s, 3H, CH3), 3.20 (br
d, 2H, allyl CH2), 2.75 (dd, 1H, CH2OtBu), 2.43 (dd, 1H, CH2OtBu), 1.28 (s, 9H, tBu),
13
1.09 (d, 3H, CH3); C NMR (CDCl3) 170.8 (CO), 151.9 (C), 144.7 (C), 140.0 (C),
139.2 (CH), 132.1 (CH), 130.3 (C), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.0 (CH),
118.7 (C), 116.0 (CH2), 100.7 (CH2), 80.9 (C), 58.7 (CH), 56.7 (CH), 54.0 (CH3), 49.7
1,1-Dimethylethyl (3R)-3-[3-bromo-5-chloro-2-(methoxymethoxy)phenyl]-3-
anhydrous CH2Cl2 (2.5 mL) was degassed. This was added catalytic
mg, 2.787 mmol). The solution was stirred at 30-35 C for 2 h. After cooling to room
temperature the CH2Cl2 was removed in vacuo and replaced by TBME (10 mL). The
ethereal solution was extracted with saturated K2CO3 (2 x 2 mL) then filtered to aid
separation of an emulsion. The TBME solution was dried (MgSO4), filtered and
concentrated to give a pale-yellow oil (480 mg) that contained 13% diallyldimethyl
barbituric acid. The corrected yield of product was 91%: IR (thin film) 3081, 2977,
2932, 2830, 1726, 1681, 1451, 1433, 1381, 1369, 1312, 1295, 1256, 1199, 1158, 1073,
5.25 (dd, 2H, MOM CH2), 4.62 (dd, 1H, NCH), 3.60 (q, 1H, NCHCH3), 3.45 (s, 3H,
CH3), 2.59 (dd, 1H, CH2OtBu), 2.38 (dd, 1H, CH2OtBu), 1.35 (s, 9H, tBu), 1.31 (d, 3H,
13
CH3); C NMR (CDCl3) 171.1 (CO), 152.0 (C), 146.0 (C), 140.5 (C), 131.8 (CH),
131.2 (C), 130.7 (C), 128.7 (CH), 127.8 (CH), 127.3 (CH), 127.0 (CH), 100.7 (CH2),
81.2 (C), 58.2 (CH3), 56.0 (CH), 52.1 (CH), 43.1 (CH2), 28.5 (CH3), 23.3 (CH3); mass
To a solution of 8 (100 mg, 0.2 mmol) in methanol/water/acetic acid (3.5 mL, 85:12:3)
was added palladium on carbon (40 mg, 10%, 50% Degussa wet paste). The mixture was
degassed thoroughly with nitrogen, then hydrogen and stirred at ambient for 18 hours.
The catalyst was removed by filtration through Celite and the solution concentrated.
The residue was dissolved in TBME (20 mL) and extracted with 1M hydrochloric acid (3
x 5 mL). The pH of the combined aqueous extracts was adjusted to pH 8 with potassium
carbonate. This was extracted with ethyl acetate (3 x 5 mL). The combined extracts were
dried (MgSO4), filtered and concentrated to give the amine 9 as a pale-yellow oil (44 mg,
13
79%). The loss of both halogens was confirmed by C NMR and mass spectrum
analysis: IR (thin film) 3380, 2977, 1725, 1601, 1489, 1368, 1233, 1199, 1154, 1079,
1000, 757 cm-1; 1H NMR (CDCl3) 7.31-6.85 (m, 4H, ArH), 5.16 (s, 2H, MOM CH2),
4.58 (dd, 1H, CHNH2), 3.42 (s, 3H, CH3), 2.64 (dd, 1H, CH2), 2.52 (dd, 1H, CH2), 1.55
13
(brs, 2H, NH2 + H2O), 1.37 (s, 9H, tBu); C NMR (CDCl3) 172.0 (CO), 154.8 (C),
128.6 (CH), 127.5 (CH), 122.3 (CH), 114.4 (CH), 94.8 (CH2), 81.0 (C), 56.6 (CH3), 55.5
(CH), 44.1 (CH2), 28.5 (CH3); mass spectrum (m/z, ES+) 282 (100), 226 (38), 209 (11)
(C15H24NO4 = 282).
Asymmetric Enamine Reduction
To a solution of 10 (20.0 g, 0.117 mol) in DMF (200 mL) was charged solid N-
further charge (4.16 g) of N-bromosuccinimide was added. After stirring for 1 h, the
reaction was quenched with water (500 mL) and cooled in an ice bath for 30 min. The
resulting solid was collected by filtration and washed with water (2 x 100 mL). The
crude product (28.2 g) was slurried in methanol (40 mL) for 2 hours, then cooled to < 10
C, filtered and the solid washed with methanol (2 x 10 mL) to give 22.8 g (78% yield) of
11 as a beige solid. 1H NMR (CDCl3) 12.75 (s, 1H, OH), 7.65 (d, 1H, ArH), 7.60 (d,
A solution of 11 (13.0 g, 0.052 mol) and diethyl carbonate (24.6 g, 0.21 mol) in
toluene (104 mL) was added dropwise via dropping funnel to sodium hydride (60%
dispersion in mineral oil, 4.59g, 0.115 mol) in toluene (26 mL) under a nitrogen
atmosphere, keeping the temperature below 30 C. After the addition was complete the
reaction was heated to reflux for 2 h. Caution: Vigorous gases evolution occurs at 85-90
C. After 2 h the reaction was cooled to room temperature and quenched by the addition
of 3M HCl (260 mL). To this was added ethyl acetate (200 mL), the layers separated and
the aqueous layer extracted with ethyl acetate (50 mL). The combined organic layers
were washed with saturated NaHCO3 (130 mL) and water (50 mL), dried (MgSO4) and
concentrated to a yellow solid (17.6 g): mp. 75 C; IR (nujol mull) 1715, 1633 cm-1; 1H
NMR (CDCl3) 12.35.(s,.1H, OH), 7.7 (s, 1H, ArH), 7.6 (s, 1H, ArH), 4.15 (q, 2H,
OCH2), 3.9.(s, 2H, CH2), 1.2.(t, 3H, CH3); 13C NMR (CDCl3) 197.9 (ketone CO), 166.4
(ester CO), 158.3, 139.9, 129.2, 124.6, 120.2, 113.6, 62.49 (CH2), 46.2 (OCH2), 14.4
(CH3).
Ethyl 3-(acetylamino)-3-[2-(acetyloxy)-3-bromo-5-chlorophenyl]-2-propenoate
(12). To a clear stirred solution of 11 (4.0 g, 12.5mmol) in DMF (80 mL) was added
ammonium acetate (12 g). The resultant suspension was stirred overnight (16 h) at room
temperature to afford a deep yellow suspension. The solvent were removed in vacuo at 30
o
C, the residue poured onto water (100 mL), extracted with ethyl acetate (4 x 50 mL),
washed with water (50 mL), dried (MgSO4), filtered, and the solvent removed in vacuo.
The residue was dissolved in TBME (50 mL) and hexanes added (50 mL). This was
concentrated in vacuo to approximately 60 mL, and allowed to stand for 30 min. prior to
filtration and isolation of the first crop of corresponding enamine (2.1 g). The mother
liquors were then removed in vacuo to afford a crude reaction product that was purified
by silica gel column chromatography using hexanes: ethyl acetate (3:7). Concentration in
1712, 1616, 1524 cm-1; 1H NMR (DMSO) 10.10-9.50 (br, 1H, NH/OH), 7.70 (d, 1H,
ArH), 7.50-7.70 (br, 2H, NH/OH), 4.52 (s, 1H, CHCO2Et), 4.05 (q, 2H, OCH2CH3), 1.20
13
(t, 3H, OCH2CH3); C R (DMSO) 1169.5, 157.8, 132.8, 129.0, 128.4, 123.8,
113.3, 84.5, 58.3, 14.9. A duplication of signals was observed when using CDCl3 as
1
NMR solvent. H NMR (CDCl3) 10.25-10.45 (br, 0.99H, NH/OH), 7.66 (d, 0.33H,
ArH), 7.56 (d, 0.67H, ArH), 7.37 (d, 0.33H, ArH), 7.34 (d, 0.67H, ArH), 6.45-6.65 (br,
2.01H, NH/OH), 4.92 (s, 0.67H, CHCO2Et), 4.30 (q, 0.66H, OCH2CH3), 4.20 (q, 1.34H,
The yellow solution was left stir overnight (16 h) at room temperature prior to being
poured onto saturated aqueous ammonium chloride (50 mL). This was extracted with
ethyl acetate (3 x 25 mL), the organic layer dried (MgSO4) and filtered. Removal of the
solvents in vacuo afforded a pale colored solid that was purified by silica gel column
transparent crystals: mp 131-133 oC; R (nujol mull) 1778, 1703, 1663, 1629, 1583, 1294,
1170 cm-1; 1H NMR (CDCl3) 10.89-10.82 (br, 1H, NH), 7.62 (d, 1H, ArH), 7.25 (d, 1H,
ArH), 5.11 (s, 1H, CHCO2Et), 4.22 (q, 2H, OCH2CH3), 2.30 (s, 3H, Ac), 2.14 (s, 3H,
13
Ac), 1.32 (t, 3H, t, OCH2CH3); C NMR (CDCl3) 168.8, 168.0, 148.5, 144.5, 133.6,
133.5, 133.4, 132.3, 128.3(3), 128.3(1), 117.8, 101.6, 61.6, 24.7, 20.8, 14.5.
()-Ethyl 3-(acetylamino)-3-[2-(acetoxy)-3-bromo-5-chlorophenyl]-2-propenaote
( 3). A 4-dram pressure vial containing 12 (50 mg, 0.124mmol) and methylene chloride
(2 mL) was degassed with argon. To this was added Rh-DUPHOS catalyst (5-7 mg, ca 7
nmol, ca 5-7 mol%). A small stirring bar was added and the reactor sealed inside a high-
pressure reaction vessel. An atmosphere of AR hydrogen was then introduced and the
pressure maintained at 8 bar for ca 2 minutes prior to venting. This procedure was
repeated 5 times. The high-pressure reaction vessel was then repressurized with hydrogen
(5 bar) and the contents left to stir at room temperature overnight (15-17 h). The vessel
was vented and the contents filtered through a short plug of silica gel using ethyl acetate.
The fractions were combined and concentrated in vacuo. The product was dissolved in
CDCl3 and the reaction product composition analyzed by 360 MHz 1NMR spectroscopy
reactor equipped with a reflux condenser was charged 4 (20 kg, 85 mol) and acetic
anhydride (46.7 kg, 457 mol). Triethylamine (8.59 kg, 85 mol) was charged while
maintaining 25 oC cooling on the jacket. A 20 oC temperature rise was observed and all
starting material was dissolved giving rise to a dark, reddish-brown solution. The
reaction mass was heated to 135 oC. Reflux began at 120 oC and the reaction mixture
turned completely brown. This temperature was maintained for 14 h. The solution was
then cooled to 70 oC (note the reaction mass solidifies if cooled to 65 oC) and 100 %
ethanol (8.58 kg, 186 mol) charged while maintaining 70 oC 5 oC. Water (143 kg, 7.96
kmol) was added again while maintaining a temperature of 70 oC 5 oC. The contents
were cooled over a 4 h period to 20 oC and the product mixture transferred to a 0.2 m2
Hastelloy C, jacketed, agitating Nutsche filter. The product cake was deliquored and
dried in vacuo to afford 13 (17.28 kg) in 79% yield: mp. 151-154 oC.
chloride ()-(3). To a 378 L (100 gal) pressure reactor equipped for distillation was
charged 13 (16.6 kg, 63.8 mol) and 2B ethanol (50 kg). The reactor was sealed and
anhydrous ammonia (109 kg) charged. The batch was heated to 80 oC with agitation
attaining an internal pressure of 581 psig. After 24 h, the batch was cooled to 25-30 oC
and carefully vented to another reactor configured with an acid scrubber. The reaction
mixture was allowed to sit overnight for further venting. The next morning heat was
applied to the jacket to drive off the remaining ammonia. At one point vacuum was
applied to assist with the ammonia purge. Following this procedure, the
ammonia/ethanol solution was distilled to minimum stir volume, and ethanol 2B (52 kg)
charged back to the reactor. After stirring for 0.5 h, HCl (23 kg) was carefully charged to
the reaction mixture over a 2.5 h period. An exotherm from ambient to reflux was
observed during the addition. Upon completion, the temperature of the system was
increased to reflux (79 oC), maintained for 1 h. and then distillation in vacuo completed
affording approximately 190 L of distillate. Toluene (67 kg) followed by hexane (67 kg)
was added to the mixture to yield a thin, light-brown slurry. The batch was dropped
employing a 24 centrifuge, the cake washed with hexanes and then transferred to a tray
dryer where the product was dried at 40 oC for approximately 60 h to afford 17.8 kg of
mandelic acid salt. Solid (R)-(-)-mandelic acid (943 mg, 6.2 mmol) was added to a
stirred solution of racemic 3 free base (2.0 g, 6.2 mmol) in ethyl acetate (30 mL) and the
mixture was heated to reflux with stirring. The yellow solution was cooled to ambient
temperature to precipitate an off-white solid. After 1 hour the solid was filtered, washed
by displacement with ethyl acetate (2 x 4 mL) and dried to give ethyl 3-amino-3-(3-
CH(OH)CO2H), 4.58 (t, 1H, CH2CHNH), 4.03 (q, 2H, CH3CH2O), 2.85 (m, 2H,
propanoate mandelic acid salt. Ethyl acetate (19 mL) was added to ethyl 3-amino-3-(3-
the mixture was heated to reflux with stirring. The pale yellow solution was cooled to
ambient temperature, precipitating a white solid. After a 1 h the solid was filtered,
washed by displacement with ethyl acetate (2 x 2.5 mL) and dried to give purified ethyl
A second recrystallization (0.55g mandelic acid salt) from ethyl acetate (8.25 mL),
hydroxyphenyl)propanoate mandelic acid salt as a white solid (0.39g, 71%, 99% ee).
camphorsulfonic acid salt. Solid (1R)-(-)-10-camphor sulfonic acid (1.44 g, 6.2 mmol)
hydroxyphenyl)propanoate free base (2.0 g, 6.2 mmol) in isopropanol (10 mL) and the
mixture was heated to reflux with stirring. The yellow solution was cooled to ambient
temperature to precipitate an off-white solid. After a 1 h the solid was filtered, washed
(1.4 g, 41%, 53% ee). 1H NMR (DMSO) 7.70 (d, 1H, ArH), 7.52 (d, 1H, ArH), 4.90
(bt, 1H, CH2CHNH), 4.02 (q, 2H, CH3CH2O), 3.02 (m, 2H, CH2CHNH), 2.90 (d, 1H,
CSA), 2.65 (m, 1H, CSA), 2.45 (d, 1H, CSA), 2.25 (m, 1H, CSA), 2.10-1.70 (m, 1H,
CSA), 1.30 (m, 2H, CSA), 1.15 (t, 3H, CH3CH2O), 1.05 (s, 3H, CSA), 0.80 (s, 3H, CSA).
Recrystallization of ethyl 3-amino-3-(3-bromo-5-chloro-2-hydroxyphenyl)
propanoate camphorsulfonic acid salt. Isopropanol (19 mL) was added to ethyl 3-
(1.31 g, 2.4 mmol) and the mixture was heated to reflux with stirring. The pale yellow
solution was cooled to ambient temperature to precipitate a white solid. After a 1 h the
solid was filtered, washed by displacement with isopropanol (2 x 2.5 mL) and dried to
>98% ee).
Imino-Reformatsky Approach.
dry 378 L (100 gal) was charged with deadhead vacuum DMF (81 kg). Aldehyde 4
(24.5 kg 104 mol) and potassium carbonate (14.4 kg, 104 mol) were charged via the
manway. The reactor was sealed and capped with nitrogen. After 20 min of agitation,
methoxyethoxymethyl chloride (13.7 kg, 110 mol) was charged via a small pump and
nalgene addition line while maintaining an internal temperature of 20-25 oC. Caution,
MEM chloride is clear, flammable, toxic lachrymator and may cause heritable genetic
damage. Avoid inhalation and contact. The reaction mixture was agitated for 3.5 h.
To a clean 757 L (200 gal) reactor was charged 397 L (105 gal) of water. The
reaction mixture was transfer to the reactor containing the water. The product begins to
precipitate from solution. After complete addition, the slurry was stirred for 1-2 h. The
2 loads. Each cake was washed twice with water (23 L) and spin dry as much as
possible. The wet cake was dried in a vacuum tray dryer at 15-20 oC for 16 h. Note do
not heat the dryer since the product melts at 31-33 oC. Isolated was 31.1 Kg (92%) of
a clean, dry, inerted 757 L (200 gal) jacketed reactor equipped with reflux condenser was
charged zinc (45.6 kg), THF (327 kg), and 1,2-dibromoethane (4.0 kg). Agitation was
initiated, the reaction contents heated to reflux (ca. 67 oC) and held at reflux for at least 1
h. The contents were cooled to 50 oC, then t-butyl bromoacetate charged in the
following sequence 15.5 kg, 15.5 kg, 31.0 kg, 31.0 kg, and 31.0 kg. An exotherm was
observed with each charged and that exotherm allowed to subside before addition of the
next aliquot. Caution. Failure to follow this charge protocol may result in an
uncontrollable exotherm. After complete addition of the t-butyl bromoacetate, the batch
was held at 50 oC for at least 1 h, cooled to 0 oC and no more than 45% by weight (ca.
147 kg) removed in vacuo. Note removal of too much solvent may result in aggressive
precipitation and stop the agitator. NMP (123 kg) was added to the resulting
concentrate and the reagent solution cooled to 15 oC. Note the reagent is not stable in
-(S)--[(E)-[[3-bromo-5-chloro-2-[(2-methoxyethoxy)methoxy]phenyl]methyl-
ene]amino]phenylethanol (15). To a clean, dry and inerted 2839 L (750 gal) glass-
lined reactor was charged 14 (240 kg, 742 mol) and NMP (221 kg). The contents were
stirred for 15 min and batch temperature maintained at 25 C. Note the dissolution is
mol) and NMP (221 kg). The contents were stirred for 15 min and batch temperature
solution was transferred to the 14 solution and the mixture stirred for at least 24 h. Once
complete, the product solution was dried employing a column of molecular sieves (180
kg) giving rise to a product solution with 0.4 wt. % moisture. The solution was placed
1,1-Dimethylethyl (S)-3-bromo-5-chloro-2-[(2-methoxyethoxy)methoxy]--[[(1S)
was transferred to the Reformatsky reagent solution over 4 h period while maintaining a
In a separate vessel was prepared the quench solution by charging water (1090 Kg),
NH4Cl (266 Kg) and 37% HCl (62 kg). This mixture was stirred until the ammonium
chloride dissolved and then precooled to 5 oC. Note this was a temperature adjustment
to aid in controlling the exotherm of the subsequent quench. Be mindful that cooling
does cause some precipitation of NH4Cl. Transfer the quench solution slowly into the
the addition was complete, the contents were warmed the contents to 20 C. Charge
MTBE (800 kg) and stir for 30 minutes. The agitation was stopped and the contents
allowed to settle for 1 hour. Note the organic and aqueous layers are similar in color.
Transfer the aqueous layer to another vessel and charge MTBE (425 kg) to the vessel
containing this aqueous layer. This was stirred for 20 min. and allowed to settle for 20
The combined organic extracts were washed with 19 wt. % aqueous NH4Cl (562 kg),
water (600 L) and 23 wt. % aqueous NaCl (630 kg). The resulting product solution was
vacuum distill until an internal of 45 C was reached. NOTE the vacuum was
approximately 2 psia. The contents were allowed to cool to 25 C and methanol (411 kg)
charged. The methanol solution of 15 was cooled to 0-5 oC and used without further
purification.
1,1-Dimethylethyl (3S)-3-[3-bromo-5-chloro-2-(methoxyethoxy)phenyl]-3-[[1-
periodate (319 kg, 1490 mol) and methanol (686 kg). Stirring was initiated and the
contents heated to 30 C. To this was charged 33 wt. % methylamine in ethanol (84.8 kg,
900 mol). The aforementioned methanol solution of 15 was charged and held at 30 oC
for 12 h. Note the 15 charge needs to occur within 1 hour of the methylamine charge;
otherwise loss of conversion is observed. After the 12 h hold, ethyl acetate (2622 kg) was
The filter was pre-coated with Celite (34 kg), then the inorganics filtered off. The
filter cake was washed with ethyl acetate (379 kg) and the organic extracts combined.
The solids were disposed of. The system was vacuum distilled until minimum stir
volume or until batch temperature 40 C was reached. Note potential excess methylamine
may need to be scrubbed from the distillate. To this was charged ethyl acetate (2622 kg)
and vacuum distilled again until minimum stir volume or until a batch temperature 40 C
was reached until the methanol content was 2.5 wt. % by GC. Note the methanol content
To the reaction mixture was charged ethyl acetate (1880 kg). The solution was stirred
for 10 min, then water (1487 kg) added. This mixture was stirred for 30 min., agitation
halted and allowed to settle for 30 min. The aqueous phase was transferred to a separate
vessel and back extracted with ethyl acetate (540 kg). The aqueous phase was disposed
pentahydrate (596 kg) solution. This was charged to the organic phase, stirred for 20
min., allowed to settle for 60 min and the aqueous phase disposed of. The organic phase
was then washed with 24 wt. % brine solution (625 kg) and the aqueous wash disposed
of. The organic phase was distilled in vacuo to a minimum stir volume or until the batch
temperature reached 40 C. Following this distillation ethanol (743 kg) was charged to
the reaction mixture and this distilled to a minimum stir volume or until the batch
temperature reached 40 C. Finally, ethanol (1390 kg) was charged giving rise to a
solution of 17, which was used without further purification. Note the ethyl acetate
content should be 0.7% and the water 0.2%. Isolated sample: IR (thin film): 2977,
2930, 2882, 1726, 1642 cm-1; 1H NMR (CDCl3) 8.35 (s, 1H, ArH), 7.70 (m, 2H, ArH),
7.58 (s, 1H, ArH), 7.20 (m, 4H, ArH), 5.17 (m, 3H, OCH2CH2O and CH2CHN), 4.00 (m,
2H), 3.55 (m, 2H), 2.80 (dd, 1H, CH2CHN), 2.72 (dd, 1H, CH2CHN), 1.27 (s, 9H, tBu);
13
C NMR (CDCl3) 177.4 (C, CO), 170.2 (CH, ArCHN), 158.2 (C, Aryl), 147.7 (C,
Aryl), 143.6 (C, Aryl), 139.2 (CH, Aryl), 138.6 (CH, Aryl), 138.2 (C, Aryl), 136.2 (CH,
Aryl), 134.8 (CH, Aryl), 125.2 (C, Aryl), 107.1 (CH2, OCH2O), 88.3 (C, tBu), 79.4 (CH2,
OCH2CH2O), 77.5 (CH2, OCH2CH2O), 72.4 (CH, CH2CHN), 66.7 (CH3, OMe), 51.3
monohydrate (184 kg, 967 mol). The ethanol solution of 17 was transferred to this vessel
and agitation initiated. The reaction mixture was heated to reflux (70-78 oC) and held at
reflux for 8 h. The contents were cooled to 10 C and then vacuum distilled to minimum
stir volume or until the batch temperature reached 40 C. Note removing too much solvent
will give rise to an extremely viscous/solids slurry. Once the distillation was complete,
THF (642 kg) was charged, the contents cooled to 10 oC and vacuum distillation resumed
to either a minimum stir volume or until batch temperature reached 40 C. After this
distillation was complete, THF (658 kg) was charged and the contents heated to 65 C.
Once the product was dissolved, heptane (1015 kg) was charged at such a rate as to
maintain 65 C. Note product will precipitate during heptane addition. The contents
To a separate vessel was charged acetone (932 kg). The acetone was cooled to 0 C.
The (S)-3 ethyl ester, p-TsOH salt was filtered and the product cake washed with the cold
acetone in 3 equal portions. The wet cake of (S)-3 ethyl ester, p-TsOH was dried in
vacuo in a tumble dryer at 25 C until a LOD of less than 1.0% was achieved affording
100 kg (51%) of (S)-3 ethyl ester, p-TsOH: m.p. 118.1 C; IR (nujol mull) 1724, 1598,
1327 cm-1; 1H NMR (DMSO) 7.73 (s, 1H, ArH), 7.50 (d, 3H, ArH), 7.10 (d, 2H, ArH),
4.90 (m, 1H, CH2CHN), 4.06 (q, 2H, CH3CH2O), 3.00 (m, 2H, CH2CHN), 2.30 (s, 3H,
CH3-Ar), 1.15 (t, 3H, CH3CH2O); 13C NMR (DMSO) 169.4 (C, CO), 151.1 (C, Aryl),
146.1 (C, Aryl), 137.9 (C, Aryl), 132.6 (CH, Aryl), 128.4 (CH, Aryl), 127.6 (CH, Aryl),
125.8 (CH, Aryl), 124.5 (C, Aryl), 112.8 (C, Aryl), 61.0 (CH2, CH3CH20), 46.2 (CH,
CH2CHN), 37.5 (CH2, CH2CHN), 21.1 (CH3, Me-Ar), 14.2 (CH3, CH3CH2O). ee >98%
(chiral HPLC). Anal. Calcd for C18H21BrClNO6S: C, 43.69; H, 4.27%; N, 2.83; Br,
16.15; Cl, 7.16; S, 6.48. Found: C, 44.47; H, 4.46; N, 2.66; Br, 15.15; Cl, 7.05%, S, 6.52.