Organic Process Research & Development
ARTICLE
(275 mmHg pressure). The fraction with a boiling range of
109ꢀ110 °C was collected, to afford the title compound as a
colorless oil, (75.5 kg, 24% yield, 92% chemical purity, enantio-
meric purity 96% ee). 13C NMR (100.6 MHz, CDCl3) δ 68.10,
35.50, 35.36, 19.98, 16.72, 14.12.
2H), 3.13ꢀ3.01 (m, 1H), 2.75ꢀ2.49 (m, 2H), 1.80ꢀ1.06
(m, 10H), 0.98ꢀ0.86 (m, 6H); 13C NMR (100.6 MHz, CDC13)
δ 169.69, 169.65, 121.28, 120.99, 61.14, 39.38, 39.15, 38.98,
37.67, 37.23, 36.95, 30.54, 30.47, 25.67, 25.45, 19.78, 19.61,
19.53, 18.56, 14.13, 14.05.
(R)-2-Methylpentyl methanesulfonate. A 4000 L reactor was
charged with (R)-2-methylpentan-1-ol (260 kg, 2545 mol),
TBME (2000 L), and cooled to ꢀ10 to 0 °C. Methanesulfonyl
chloride (310 kg, 2705 mol) was charged, and then Et3N (310 kg,
3063 mol) was added while maintaining the internal temperature
at 0 to 10 °C. After the addition was complete, the reaction
mixture was warmed to 15 to 25 °C and stirred at this
temperature for at least 1 h until complete by GC analysis. A
solution of aq HCI (88 kg of conc. HCl in 700 L of water) was
then added to the reaction mixture. The resulting mixture stirred
for at least 15 min, settled for at least 15 min and then the lower
aqueous phase was removed. The upper organic phase was
washed with water (790 L) and aqueous sodium bicarbonate
(67 kg of sodium bicarbonate in 840 L of water). The solution
was then concentrated under vacuum to remove the TBME to
afford the title compound as an oil (472 kg, 95% yield). 1H NMR
(400 MHz, CDC13) δ 4.07ꢀ3.93 (m, 2H), 2.97 (s, 3H),
1.91ꢀ1.80 (m, 1H), 1.42ꢀ1.09 (m, 4H), 0.94 (d, J = 6.57 Hz,
3H), 0.87 (t, J = 6.56 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 74.73, 37.01, 34.81, 32.65, 19.71, 16.29, 14.04.
Method B (5R)-3-Cyano-5-methyloctanoic Acid Ethyl Ester
16. A 250-mL flask was charged with LiCl (3. 89 g, 0.09 mol), water
(7 mL), and DMSO (72 mL). (20R)-2-Cyano-2-(20-methylpen-
tyl)succinic acid diethyl ester (25.4 g, 0.07 mol, 78.74% by GC) was
charged, and the mixture was heated to 135ꢀ138 °C and stirred at
this temperature for at least 24 h, until complete by GC analysis.
After the reaction was cooled to 25ꢀ35 °C, heptane (72 mL),
saturated NaCl (72 mL) and water (72 mL) were added, and the
mixture stirred for at least 15 min, settled for at least 15 min, and
then the lower aqueous phase was washed with heptane (100 mL).
The combined organic phases were concentrated under vacuum to
afford the title compound as an orange oil (13.0 g, 85% yield).
(5R)-3-Cyano-5-methyloctanoic Acid Sodium Salt 17. A
4000-L reactor was charged with (5R)-3-cyano-5-methyloctanoic
acid ethyl ester (250 kg, 1183 mol) and THF (450 kg). An
aqueous solution of NaOH was prepared (190 kg of NaOH in 350
L of water) and then added to the THF solution. The resulting
solution was stirred at 20ꢀ30 °C for at least 2 h, until the reaction
was complete by GC analysis. After this time, THF was removed
by vacuum distillation to afford an aqueous solution of the product
17, which was used immediately in the next step.
(5R)-3-Aminomethyl-5-methyloctanoic Acid Sodium Salt. A
120-L autoclave was charged with sponge nickel catalyst (3.2 kg,
Johnson Matthey A7000) followed by an aqueous solution of
(5R)-3-cyano-5-methyloctanoic acid sodium salt (15 kg in
60 L of water,) and the resulting mixture was hydrogenated
under 50 psi of hydrogen at 30ꢀ35 °C for at least 18 h, or
until hydrogen uptake ceased. The reaction was then cooled to
20ꢀ30 °C, and the spent catalyst was removed by filtration
through a 0.2 μm filter. The filter cake was washed with water
(2 ꢁ 22 L), and the resulting aqueous solution of the title
compound was used directly in the next step without isolation.
(5R)-3-Aminomethyl-5-methyloctanoic Acid 14. A 4000-L
reactor was charged with an aqueous solution of (5R)-3-amino-
methyl-5-methyloctanoic acid sodium salt (150 kg in 1000 L of
water) and cooled to 0ꢀ5 °C. Glacial acetic acid was added until
the pH was 6.3ꢀ6.8. To the mixture was added anhydrous EtOH
(40 kg). The resulting slurry was heated to 65ꢀ70 °C for less
than 20 min and was cooled to 0ꢀ5 °C over 3 h. The product was
collected by filtration to afford the product 14 as a water-wet cake
(76 kg, 97% yield corrected for purity, 10% water by KF), which
was used directly in the next step. 1H NMR (400 MHz, CD3OD)
δ 4.97 (bs, 3H), 3.00ꢀ2.74 (m, 2H), 2.48ꢀ2.02 (m, 3H),
1.61ꢀ1.03 (m, 7H), 0.94ꢀ086 (m, 6H); 13C NMR (100.6
MHz, CD3OD) δ 181.10, 181.07, 46. 65, 45.86, 44.25, 43.15,
42.16, 41.64, 41.35, 33.45, 31.25, 31.20, 21.45, 21.41, 20.52,
20.12, 15.15, 15.12.
(20R)-2-Cyano-2-(20-methyl-pentyl)succinic Acid Diethyl Ester
15. A 4000 L reactor was charged with (R)-2-Methylpentyl
methanesulfonate (245 kg, 1359 mol), 2-cyanosuccinic acid
diethylester (298 kg, 1495 mol) and anhydrous EtOH (1300 kg).
Sodium ethoxide (506 kg, 21 wt % in EtOH) was added. The
resulting solution was heated to 70ꢀ75 °C and the mixture
stirred at this temperature for at least 18 h until complete by GC
analysis. After the reaction was complete, a solution of aqueous
HCl (32 kg of conc. HCl in 280 L of water) was added to the
reaction mixture until the pH was <2. Additional water (400 L)
was added, and the reaction mixture was then concentrated
under vacuum to remove the ethanol. TBME (1000 kg) was
added and the mixture was stirred for at least 15 min, settled for at
least 15 min and then the lower aqueous layer was back extracted
with TBME (900 kg). The combined organic phases were con-
centrated under vacuum to afford the product 15 as a dark oil
(294 kg, 79% yield). 1H NMR (400 MHz, CDCl3) δ 4.29 (q, J =
7.07 Hz, 2H), 4.18 (q, J = 7.07 Hz, 2H), 3.03 (dd, J = 6.6, 7.1 Hz,
2H), 1.93ꢀ1.61 (m, 3H), 1.40ꢀ1.20 (m, 10H), 0.95ꢀ0.82 (m,
6H); 13C NMR (100.6 MHz, CDC13) δ 168.91, 168.67, 168.59,
168.57, 119.08, 118.82, 62.95, 62.90, 44.32, 44.19, 42.21, 42.02,
39.77, 39.64, 30.05, 29.91, 20.37, 19.91, 19.66, 13.99.
Method A (5R)-3-Cyano-5-methyloctanoic Acid Ethyl Ester
16. A 4000-L reactor was charged with NaCl (175 kg, 3003 mol),
tetrabutylammonium bromide (33.1 kg, 103 mol), water
(87 L), and DMSO (1000 kg). (20R)-2-Cyano-2-(20-methylpen-
tyl)succinic acid diethyl ester (243 kg, 858 mol) was charged, and
the mixture was heated to 135ꢀ138 °C and stirred at this
temperature for at least 48 h, until complete by GC analysis.
After the reaction was cooled to 25ꢀ35 °C, heptane (590 kg) was
added, and the mixture stirred for at least 15 min and settled for at
least 15 min, and then the lower aqueous phase was removed.
The upper organic phase was washed with water (800 L). The
heptane solution containing the product was decolorized with
carbon and concentrated under vacuum to afford the title
compound as an orange oil (133.9 kg, 74% yield corrected for
(3S,5R)-3-(Aminomethyl)-5-methyloctanoic Acid 3 via (S)-
Mandelic Acid Resolution. A 4000-L reactor was charged with
water wet (10%) (5R)-3-aminomethyl-5-methyloctanoic acid
(76 kg, 365 mol), (S)-mandelic acid (34. Eight kg, 229 mol),
anhydrous EtOH (1780 kg), and water (115 L). The resulting
mixture was heated to 65ꢀ70 °C and stirred until the solids
dissolved. The solution was then cooled to 0ꢀ5 °C over 2 h and
stirred at this temperature for an additional 1 h. The product was
collected by filtration, and the cake was washed with cooled
EtOH (3 ꢁ 60 kg). The crude damp product (18 kg, 24% yield)
1
purity). H NMR (400 MHz, CDC13) δ 4.20 (q, J = 7.07 Hz,
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dx.doi.org/10.1021/op2001832 |Org. Process Res. Dev. 2011, 15, 1315–1327