Organic Process Research & Development
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with constant stirring and maintained for 9 h. The mass was
allowed to cool to 20−25 °C, and the solvent was distilled
under vacuum at 40−45 °C until 70−75% of the solvent was
removed. The solution was cooled to 0−5 °C, stirred for 2 h,
and filtered. The filtered solid was washed with portions of cold
isopropyl alcohol (0−5 °C) and dried under vacuum to yield
portions of hexane, and dried under vacuum at 25−30 °C to
give the desired product of formula 1 (9.06 kg, 65% yield,
1
HPLC purity of 95%). H NMR (CDCl ) δ 2.63 (2H, t, J = 7.8
3
Hz), 2.94 (2H, t, J = 7.8 Hz), 3.90 (3H, s), 3.91 (3H, s), 6.57
(1H, d, J = 8.7 Hz), 7.90 (1H, d, J = 8.7 Hz), 13.16 (1H, s).
(+)-5-Methoxy-11-methylene-13-oxo-6-aza-tricyclo-
2
,7
the pyridine of formula 4 (7.9 kg, 43% yield, HPLC purity
[7.3.1.0 ]trideca-2(7),3,5-triene-1-carboxylic Acid
Methyl Ester (7). The chiral ligand SL-T002-1 (42.6 g, 2
mol %), allyl palladium chloride dimer (11.2 g, 1 mol %), and
acetone (2.8 L) were combined and stirred at 20−25 °C for 1 h
under a nitrogen atmosphere. To the mixture was added 1,3-
diacetoxy-2-methylenepropane (0.524 L, 1.0 equiv) and
acetone (0.70 L), and the new mixture was stirred and
maintained at the same temperature for 1 h. A mixture of the
purified keto ester of formula 1 (0.70 kg, 1.0 equiv), 1,1,3,3-
tetramethylguanidine (0.84 L, 2.2 equiv), and acetone (3.5 L)
was added to the above solution in lots over a period of 30 min
at 20−25 °C. The resulting mixture was then stirred at the
same temperature for 1 h under a nitrogen atmosphere. At this
time, a sample for HPLC indicated <1% of the starting material
(1) remained. Acetone was then distilled off under vacuum at
40−45 °C, and the residues were passed through a bed of silica
gel, eluting with hexane and ethyl acetate mixtures to remove
the catalyst and ligand. The solvent was then distilled
completely to give the crude product of formula (7) (0.70
kg, 82% yield and HPLC purity of 70%). This crude material
(0.70 kg) was stirred with isopropyl alcohol (2.8 L) at 20−25
°C for 30 min. The resulting solid was filtered and washed with
isopropyl alcohol (0.35 L) and the material dried under vacuum
1
>
98%). H NMR (CDCl ) δ 1.90 (2H, t, J = 6.6 Hz), δ 2.67
3
(
2H, s), δ 2.90 (2H, t, J = 6.6 Hz), δ 3.98 (4H, s), δ 6.35 (1H,
d, J = 9.3 Hz), δ 7.12 (1H, d, J = 9.3 Hz).
′,8′-Dihydro-2′methoxyspiro[1,3-dioxolane-
,6′(5′H)-quinoline] (5). The pyridone of formula 4 (17 kg,
.0 equiv) was combined with dichloromethane (170 L), 1 M
7
2
1
sodium hydroxide solution (90.6 L, 1.1 equiv) and benzyl-
triethylammonium chloride (9.35 kg, 0.5 equiv) and stirred at
2
0−25 °C for 15 min. Silver carbonate (22.6 kg, 1.0 equiv) was
added followed by iodomethane (15.3 L, 3.0 equiv) at 20−25
C and stirred for 5 h at the same temperature. An in-process
°
analysis by HPLC showed <0.1% starting material (4). Workup
was carried out by layer separation followed by filtration
through filter aid and distillation of the dichloromethane layer
to yield the O-methylated compound of formula 5 (16.5 kg,
1
9
2% yield, HPLC purity of 92%). H NMR (CDCl ) δ 2.01
3
(
3
(
2H, t, J = 7.5 Hz), δ 2.90 (2H, s), δ 3.01 (2H, t, J = 7.5 Hz), δ
.89 (3H, s), δ 4.04 (4H, s), δ 6.52 (1H, d, J = 6 Hz), δ 7.25
1H, d, J = 6 Hz).
-Methoxy-7,8-dihydro-5H-quinolin-6-one (6). The O-
methylated compound 5 (16 kg) was combined with water
2
(
144 L) and phosphoric acid (88%, 64 L) and stirred at 20−25
°
C for complete dissolution. The solution was slowly heated to
7
at 35−40 °C to give the pure product as a white solid (0.385
1
5−80 °C and maintained at that temperature for 3 h,
kg, 45% yield and HPLC purity of 99.8%). H NMR (CDCl ) δ
3
whereupon HPLC analysis indicated <1% of the starting
2.55−2.64 (2H, m), 2.77−2.83 (1H, m), 2.95−2.99 (1H, m),
3.08−3.20 (2H, m), 3.46 (1H, dd, J = 18.0, 6 Hz), 3.82 (3H, s),
3.89 (3H, s), 4.50 (1H, d, J = 3.0 Hz), 4.84 (1H, d, J = 3.0 Hz),
6.59 (1H, d, J = 9 Hz), 6.99 (1H, d, J = 9 Hz).
material (5) remained. The reaction mass was cooled to 5−10
°
C and the pH adjusted to 7.0−7.5 by addition of 59% sodium
hydroxide solution. The resulting solution was then extracted
with ethyl acetate (three times with 64 L each time) and
distilled to yield the ketone compound of formula 6 as a brown
(+)-5-Methoxy-11-methyl-13-oxo-6-aza-tricyclo-
2
,7
[7.3.1.0 ]trideca-2(7),3,5,10-tetraene-1-carboxylic Acid
Methyl Ester (2). To a solution of the purified compound of
formula 7 (0.586 kg) in ethylene dichloride (5.86 L) was added
trifluoromethanesulfonic acid (0.586 L) at 20−25 °C, and the
solution was stirred for 1 h at the same temperature. An in-
process analysis by HPLC showed <0.1% starting material (7)
at this time. The reaction mixture was cooled to 10−15 °C and
neutralised with 10% sodium bicarbonate solution (8.79 L).
The layers were separated, and the aqueous layer was extracted
with additional ethylene dichloride (1.81 L). The organic layers
were combined, dried over anhydrous sodium sulphate, and
distilled to dryness under vacuum at 40−45 °C to give the
crude olefinic ester of formula 2. The crude material was stirred
with heptanes (mixed isomers, 0.525 L) at 90−95 °C for 30
min and hot filtered at 80−85 °C. After cooling to 20−25 °C,
the solution was allowed to rest without agitation for 2 h. The
supernatant liquid was decanted, and the product crystals were
isolated by stirring with heptanes (0.586 L), followed by
filtration and washing with portions of heptanes (0.586 L). The
product was dried at 35−40 °C to give compound of formula 2
1
solid (12.64 kg, 98% yield, HPLC purity of 92%). H NMR
(
3
(
CDCl ) δ 2.65 (2H, t, J = 6 Hz), δ 3.15 (2H, t, J = 6 Hz), δ
3
.51 (2H, s), δ 3.93 (3H, s), δ 6.61 (1H, d, J = 6 Hz), δ 7.31
1H, d, J = 6 Hz).
,6,7,8-Tetrahydro-2-methoxy-6-oxo-5-quinolinecar-
5
boxylic acid methyl ester (1). Sodium hydride (50%, 3.42
kg, 1.2 equivalents) and dimethyl carbonate (157.5 L) were
heated to 85−90 °C under a nitrogen atmosphere, and the
ketone of formula 6 (10.5 kg, 1.0 equivalent) diluted with
dimethyl carbonate (157.5 L) was added over a period of 1.5 h.
After addition, the reaction mixture was maintained at the same
temperature for approximately 30 min. A sample for HPLC
showed <1% of the ketone starting material (6) remained.
Dimethyl carbonate was then distilled off completely under
vacuum at 40−50 °C and the residue was cooled to 10−15 °C.
Chilled water was added and the residue dissolved completely.
The pH was adjusted to 2−3 by addition of 5 M HCl (∼20 L)
and extraction was performed with ethyl acetate (once with 42
L and then twice with 21 L). The solvent was distilled off
completely to give the crude β-keto ester of formula 1. The
crude ester was dissolved in 105 L 5% ethyl acetate/hexane
mixture by heating at 60−65 °C, and the resulting mixture was
allowed to cool to 20−25 °C and filtered. The filtrate was
evaporated to dryness under vacuum at 40−45 °C, and the
resulting residue was stirred with 31.5 L hexane for 30 min at
1
(0.469 kg, 80% yield, HPLC purity of >99%). H NMR
(CDCl ) δ 1.63 (3H, s), 2.55 (1H, d, J = 17 Hz), 3.15−3.21
3
(2H, m), 3.36−3.44 (2H, m), 3.76 (3H, s), 3.91 (3H, s), 5.42−
5.45 (1H, m), 6.63 (1H, d, J = 9 Hz), 7.12 (1H, d, J = 9 Hz).
(E)-(+)-11-Ethylidene-9,10-dihydro-2-methoxy-7-
methyl-5,9-methanocyclo-octa[b]pyridine-5(6H)-car-
boxylic Acid Methyl Ester (8). Ethyltriphenylphosphonium
20−25 °C. The product was collected by filtration, washed with
6
40
dx.doi.org/10.1021/op200360b | Org. Process Res. Dev. 2012, 16, 635−642