Organic Process Research & Development
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vacuum-dried under N2 at rt to afford trans-acid-lactam MEA
salt 18 as a white solid (154.5 g, KF ∼ 0.17%; 98 wt %; 91.2%
yield, > 97% de trans). Mother liquor/washes (1600 mL)
contained about 3.5% product. The product could be dissolve
in D2O without epimerization for NMR analysis. Dissolving the
product in CD3OD led to complete epimerization to 1:1
filtration, washing with THF (2 mL), and vacuum drying at rt
under N2 for >6 h to afford 492 mg of piperidinol 3·HCl (70%
yield) with trans:cis ratio >99.9:0.1. Losses to ML/washes were
2.5% (trans:cis = 68:32). All analytical results are consistent
with the reported values.3 HPLC method 1: Zorbax Eclipse
Plus C18 50 × 4.6 nm 1.8 um; A = acetonitrile, B = 0.1% aq.
H3PO4; 5% A to 95% A over 5 min hold for 2 min; flow rate =
1.5 mL/min; temp 25 °C; wavelength = 210 nm; retention
times, 1.46 min = cis-hydroxy-lactam 9, 1.59 min = trans-
hydroxy-lactam 9, 1.60 min = cis-acid-lactam 17, 1.72 min =
trans-acid-lactam 17. HPLC method 2: Atlantis dC18, 250 ×
4.6 mm, 5 μm; A: 0.1% TFA in water, B: 0.1% TFA in
acetonitrile; 0 min, 2% B; 5 min, 2%B; 12 min, 50% B; 20 min,
70% B; flow rate = 1 mL/min; 15 °C; Corona detecor;
retention times, 8.57 min = trans-3, 8.89 min = cis-3.
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mixture within minutes. MEA salt 18: H NMR (500 MHz,
D2O) 3.74 (m, 2H), 3.64 (m, 1H), 3.56 (s, 3H), 3.25 (m, 2H),
3.21 (dd, J = 8.5, 6.7 Hz, 1H), 2.21 (m, 1H), 2.03−1.89 (m,
2H), 1.45 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H); 13C NMR (126
MHz, D2O) 178.8, 173.0, 67.8, 58.2, 51.1, 48.4, 38.9, 27.8, 23.9,
21.2. HRMS (ESI) m/z calcd for C10H20N2O4H [M + H]+
233.1501, found 233.1592. HPLC method: Zorbax Eclipse Plus
C18, 50 × 4.6 mm, 1.8 μm; A = 0.1% H3PO4 in water, B =
acetonitrile; 5% B to 95% B over 5 min then hold for 2 min;
flow rate = 1.5 mL/min; temp. 25 °C; detection = 210 nm;
retention times: 1.60 min = cis-acid-lactam 17, 1.72 min = trans-
acid-lactam 17, 2.45 min = cis-ester-lactam 8b, 2.49 min = trans-
ester-lactam 8b.
Thermodynamic Stability of MEA Salt 18. The stability and
solubility of 18 were examined in the following three solvent
solutions: (1) 1 vol % water in MeCN; (2) 1.7 vol % water was
prepared by adding 0.43 mL water to 25 mL MeCN; and (3)
1.5 mL of heptane was added to 10 mL of THF. 80 mg of acid
lactam MEA salt 18 (∼95% de, 98.6 wt %) each was slurried in
1.5 mL of solvents 1 and 2 above. 50 mg of the acid lactam was
slurried in 1 mL of solution 3. The samples were stirred and
sampled at certain period of time (2, 4, 6, and 72 h). The
slurries were centrifuged first to compact the solids. The
supernatant solutions were then filtered through 0.2 μm Nylon
filter, and the solids were dried for 15 min under vacuum at
room temperature. The solutions were analyzed for total
diastereomer concentration, and the solids were analyzed for de
(see Table 2).
Preparation of ((3R,6R)-6-Methylpiperidin-3-yl)methanol
Hydrochloride (3). Method 1. To a vessel was charged acid-
lactam MEA salt 18 (94.5% de; 98.6 wt %) (1 g, 4.24 mmol)
and heptane (5.00 mL). The suspension was cooled to −10 °C
under N2. 7 equiv of 1 M BH3·THF (29.7 mL, 29.7 mmol) was
slowly added over 20 min at < −5 °C. The resultant clear
solution was stirred at −10 °C for 10 min, rt for 1 h, then at 60
°C under a condenser and N2. After heating for 17−20 h,
HPLC assay showed the complete consumption of SM and
about 4% alcohol-lactam intermediate (i.e., 96% conversion).
After aging at rt for additional 6 h, the reaction solution was
cooled to 2 °C, then slowly added 6 N HCl (7.07 mL, 42.4
mmol) over 10 min at <15 °C. The slurry was stirred at rt
overnight (or at least for 2 h). The mixture, pH ∼ 0−1, was
made alkaline (pH 13−14) with addition of 10 N NaOH
(30%) (7.22 mL, 72.2 mmol) in one portion, which
exothermed to 39 °C. The resulting slurry was filtered and
washed with a mixture of EtOH (1.4 mL) and MTBE (3.3 mL).
The layers were separated and aqueous back-extracted with 3:1
MTBE−THF (2 × 10 mL). HPLC assay of the combined
organic showed 78% yield piperidinol with trans/cis = 98.2:1.8.
The aqueous layer showed absence of piperidinol. Organic was
dried over Na2SO4, filtered, and washed with 20 mL MTBE. It
was concentrated to dryness, and the oil was flushed with 2 ×
10 mL of 2-propanol. The resulting 0.78 g solid−oil was
dissolved in 2 mL of THF, then seeded with piperidinol HCl
salt 3 (2 mg). 4.5 N HCl in 2-propanol (0.849 mL, 3.82 mmol)
was slowly added. Crystallization was initiated immediately, and
it was stirred at rt overnight. The product was isolated by
Preparation of ((3R,6R)-6-Methylpiperidin-3-yl)methanol
Hydrochloride (3). Method 2. To a 12 L three-neck round
bottomed flask equipped with a mechanical stirrer, condenser,
thermostat, and N2 inlet was charged solid acid-lactam MEA
salt 18 (150 g, 630 mmol) and solid NaBH4 (131 g, 3469
mmol). The mixture was cooled in a −14 °C bath and added
heptane (750 mL) to give a thick slurry. Anhydrous THF
(3000 mL, KF = 61) was slowly added over 1 h keeping at <
−10 °C. To the −14 °C suspension was slowly added BF3·OEt2
(554 mL, 4407 mmol) over 1.5 h at < −9 °C. The resultant
suspension was stirred at −14 to −10 °C for 40 min, then warm
to 22 °C over 1.5 h, and then heated at 55−60 °C under a
condenser and N2 for 20 h. At of 20 h, HPLC assay showed
97% conversion based on 3% remaining starting material (LC
sample preparation involved diluting a 10 μL reaction mixture
to 1 mL with 1:1 0.1% aq. TFA: 50% AcN/H2O). The reaction
mixture was cooled to 0−5 °C and slowly added H2O (524
mL) over 25 min at <20 °C. After aging at 0−5 °C for 1 h, 12
N HCl (525 mL, 6296 mmol) was slowly added at <20 °C. The
resulting slurry (pH ∼ 0) was stirred at rt overnight. The
mixture was cooled in 17 °C bath, and 10 N NaOH (1007 mL,
10070 mmol) was slowly added over 20 min as it exothermed
to 30 °C (pH ∼ 8.5). Solid NaOH (302 g, 7.556 mol) was
added, and the mixture exothermed from 28 to 46 °C. After
stirring for 1 h as it cooled to 21 °C (pH 13−14), the mixture
was filtered, and the wet cake was washed with a mixture of
EtOH (210 mL) and MTBE (495 mL). The filtered borate salt
(∼630 g white solid) was discarded. The filtrate was transferred
to a separatory funnel, rinsed with MTBE (2 × 150 mL), and
the layers separated. The aqueous layer (pH ∼ 14) was back-
extracted with 3:1 MTBE:THF (2 × 1.5 L). The combined
organic was dried over Na2SO4, filtered, and washed with
MTBE (1 L). The combined filtrate (KF = 2.1%) was
concentrated at <25 °C to ∼200 g of brown oil. The residue
was diluted with 750 mL of 2-propanol. The resulting slurry
was concentrated to ∼200 g of oil-solid, then diluted with 750
mL of 2-propanol (supernatant KF = 0.68%), concentrated to
∼165 g oil-solid, and added 300 mL of dry THF to give total
volume ∼500 mL with KF ∼ 0.16%. The precipitated NaCl was
filtered off and washed with 100 mL THF. The combined
filtrate was concentrated to ∼135 g brown oil and diluted with
300 mL THF to give total volume ∼470 mL with KF ∼ 0.13%.
Then it was seeded with ∼50 mg of product 3, and 4.8 N HCl/
IPA (111 mL, 535 mmol) was slowly added over 40 min as it
exothermed from 20 to 37 °C. Crystallization was initiated
immediately. After stirring at rt overnight, supernatant showed
product concentration (as free base) at 18.2 mg/mL as a 25:75
trans:cis mixture. The slurry was filtered and washed with 5:1
E
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