(42.8 kg, 321 mol) in dichloromethane (201 L) is cooled to
0° C under a nitrogen atmosphere, and 3-chloropropionyl
chloride (40.0 kg, 315 mol) is added under stirring over ca.
30-60 min. Ethylene gas (ca. 13.0 kg, 464 mol) is bubbled
into the cloudy suspension for a period of 2-3 h while
keeping the temperature below 5° C. The resulting clear
mixture is slowly poured into a second 2000-L glass-lined
reactor containing toluene (217 L), concentrated HCl (22 L)
and water (130 L), keeping the temperature below 10° C.
The resulting biphasic mixture is stirred for ca. 30 min, the
lower aqueous layer is discharged, the organic layer is
concentrated under vacuum at ca. 20-40° C to obtain a
toluenic solution of 1,5-dichloropentanone with 90-95%
purity (by GLC) which is used directly in the next step.
1,5-Bis(triphenylphosphonium)pentan-3-one Dichlo-
ride (4). In a 1000-L glass-lined reactor triphenylphosphine
(165.5 kg, 631 mol), DMF (87 L) and toluene (130 L) are
consecutively charged and the resulting solution is heated
to 90° C under a nitrogen atmosphere. The above solution
of crude 1,5-dichloropentan-3-one is added over about 2-3
h at 90-100° C. The resulting suspension is stirred at 100-
105° C for 3-5 h, cooled to 20-25° C, and stirred for an
additional hour. The precipitate is filtered through a filter-
drier, washed with acetone (130 L), and vacuum-dried at
40-50° C until constant weight, obtaining the bisphos-
phonium salt 4 as a colorless crystalline solid (211.0 kg
300 MHz) δ (ppm) 1.80-2.10 (complex m, 4H, H2, and
H4), 3,6 (complex q, 2H, H1, and H5), 3.85 (complex q,
2H, H1 and H5), 4.19 (broad t, 1H, H3), 7.65-7.85 (complex
m, 30H, aromatic protons).
1,7-Dipyridin-3-yl-hepta-1,6-dien-4-ol (8). In an 800-L
stainless steel reactor crude 1,5-bis(triphenylphosphonium)-
pentan-3-ol (6) (100-105 kg, ca. 147 mol) is dissolved in
DMF (100 L) and toluene (80 L). To the resulting solution
are added pyridine-3-carboxaldehyde (32.0 kg, 298.75 mol,
2.03 equiv) and anhydrous K2CO3 (50.0 kg, 361.77 mol, 2.46
equiv). The heterogeneous mixture is heated to reflux (116°-
128° C) for 6-8 h, azeotropically distilling the water formed
and monitoring the reaction by HPLC until reaching a
conversion higher than 96%. The resulting orange suspension
is cooled to 20-25° C, transferred into a 1000-L glass-lined
reactor, and water (550 L) is added. The biphasic mixture is
strirred at 20-25° C for 30 min until complete dissolution
of the inorganic salts is observed. The organic phase is
separated and the aqueous layer extracted with toluene (100
L) and ethyl acetate (100 L). To the collected organic phases
a solution of H2SO4 (96%, 10 L) and water (170 L) is added
and the resulting biphasic mixture stirred for 30 min. The
organic phase containing the byproduct triphenylphosphine
oxide is discharged, and the acidic aqueous solution (ap-
proximately 240 L) with a product purity of 90% (by HPLC)
is used as such in the next step.
1
98.5% yield over two steps): mp 214-217° C. H NMR
1,7-Di(pyridin-3-yl)-heptan-4-ol Monosuccinate (10).
The above solution is introduced into a 1000-L stainless steel
autoclave, and moist 5% Pd/C (5.0 kg, 50% H2O) suspended
in water (20 L) is added. The vessel is purged with nitrogen
and pressurized with hydrogen gas to 4 bar. The hydrogena-
tion is carried out at 20-25° C for about 4-6 h or until
hydrogen consumption ceases. The autoclave is purged with
nitrogen, the catalyst is filtered off, and the filter cake is
washed with water (100 L). The yellow solution is transferred
into a 1000-L stainless steel reactor, and ethyl acetate (100
L) and toluene (100 L) are added. To the biphasic mixture
30% NaOH (80 L) is added until the pH reaches 10 or above.
The organic phase is separated, and the aqueous layer is
extracted with ethyl acetate (4 × 100 L). The collected
organic phases are washed with water (100 mL) and
concentrated under vacuum at 40° C/20 mbar, obtaining the
crude 1 as an orange viscous oil, having a purity of 88-
90% with 6-8% of 3-hydroxymethylpyridine (by HPLC).
The crude oil is dissolved in acetone (70 L), and the orange
solution is treated at 20-25° C with activated charcoal (1.5
kg). The suspension is filtered through a Sparkler filter with
Dicalite plates, and the filter is washed with acetone (30 L).
To the yellow solution, succinic acid (15.0 kg, 127.0 mol,
0.86 equiv) is added, and the mixture is heated to reflux for
30 min. The resulting solution is cooled to 0° C over a period
of 1 h, and the suspension is stirred at 0-5° C for another
hour. The precipitate is centrifuged, washed with acetone
(25 L), and dried in a vacuum tray-drier at 40-50° C for
ca. 8 h to deliver 1,7-di(pyridin-3-yl)-heptan-4-ol monosuc-
cinate (10) as an off-white crystalline solid (40.5 kg, 104.2
mol, 70.8% overall yield from 1,5-bis(triphenylphosphoni-
um)pentan-3-one dichloride 4), 99.2% pure by HPLC. Mp
(CDCl3, 300 MHz) δ (ppm) 3.35 (complex m, 4H, H2, and
H4), 3.92 (complex m, 4H, H1, and H5), 7.65-7.85
(complex m, 30H, aromatic protons).
1,5-Bis(triphenylphosphonium)pentan-3-ol Dichloride
(6). In a 500-L stainless steel reactor sodium borohydride
(1.7 kg, 44.94 mol, 0.305 equiv) is dissolved in demineralized
water (50 L), and the resulting solution is cooled to 0° C. In
a second 500-L stainless steel reactor 1,5-bis(triphenylphos-
phonium)pentan-3-one dichloride 4 (100.0 kg, 147.14 mol)
is dissolved in water (200 L) at 20-30° C. This solution is
added to the sodium borohydride solution over a period of
1 h while keeping the temperature below 10° C. The resulting
white suspension is stirred at 15° C for another hour and
then transferred into an 800-L glass-lined reactor. Concen-
trated HCl (10 L) is carefully added until reaching pH 2-3,
and the reaction mixture is stirred for additional 30 min at
20-25° C. The byproduct triphenylphosphine is filtered off
through a Sparkler filter which is washed with water (50
L). The clear filtrate is collected into an 800-L glass-lined
reactor and concentrated under vacuum at 50-60° C/20 mbar
to provide a slightly yellow oil which is dried by stripping
with a 1:1 toluene/DMF mixture (2 × 100 mL) and used as
such in the next step.
On a lab scale the crude oil can also be extracted with
dichloromethane (3 × 150 mL per 100 g of 1,5-bis(triphenyl-
phosphonium)pentan-3-one dichloride 4). The organic solu-
tion is concentrated under vacuum, yielding about 100-105
g of crude product as a colourless oil which crystallizes on
standing or by trituration with ethyl acetate (100 mL). The
resulting solid is highly hygroscopic, preventing routine
1
analysis. HPLC purity (area %): 98.5%. H NMR (CDCl3,
Vol. 6, No. 6, 2002 / Organic Process Research & Development
•
809