Phosphoric Acid → HCID 56640795, compound

HRID 451300Notes

Reaction equation

[CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[C:46]([O-])(O)=[O:47].[Na+].CCN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.P(=O)(O)(O)O>ClCCl>[CH2:1]([O:8][N:9]1[C:46](=[O:47])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([NH:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH2:24]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 2.5 °C

Procedure

Benzyl 4-[({(2S,5R)-5-[(benzyloxy)amino]piperidin-2-yl}carbonyl)amino]piperidine-1-carboxylate in the form of a tosylate salt (8.1 kg, 12.68 mol) was slurried in dichloromethane (108 kg), after which 5 wt % NaHCO3 (42 kg, 25.36 mol) was added and the resulting biphasic mixture was stirred vigorously for 30 minutes. The phases were separated, and the organic phase was washed with water (40.5 kg). The organic phase was then distilled at atmospheric pressure to ˜20 L, followed by the addition of DCM (108 kg). DIPEA (5.25 kg, 40.58 mol) was then added and the batch cooled to 0-5° C. Triphosgene (3.01 kg, 10.14 mol) was added in four portions, while keeping the temperature at <10° C. After 30 minutes, a dilute phosphoric acid solution (4.97 kg 85 wt % phosphoric acid in 32 kg water) was added, and the batch aged at 20° C. overnight. The phases were separated and the organic phase was washed with 5 wt % NaHCO3 (26 kg) and water (25 kg). The organic phase was then distilled at atmospheric pressure to 30 L. Ethanol (77 kg) was then added, followed by the addition of seed (10 g). (Note: Crystallization will occur without the use of seed, but the use of seed is preferred as it typically provides a more consistent product and a better yield.) The slurry was distilled in vacuo to a volume of 33 L, then heptane (55 kg) was added dropwise. The slurry was then cooled to 0° C., filtered, washed with 3:1 heptane:ethanol (30 L), and dried on the filter under nitrogen stream to give the title product (5.90 kg, 94%). 1H NMR (CDCl3) 7.35 (10H, m), 6.57 (1H, d), 5.14 (2H, s), 5.07 (1H, d), 4.92 (1H, d), 4.13 (2H, m), 3.95 (1H, m), 3.89 (1H, d), 3.31 (1H, s), 2.99 (3H, m), 2.65 (1H, d), 2.38 (1H, m), 1.94 (4H, m), 1.62 (2H, m) and 1.34 (2H, m).

Workup

customThe phases were separated
washthe organic phase was washed with water (40.5 kg)
distillationThe organic phase was then distilled at atmospheric pressure to ˜20 L
additionfollowed by the addition of DCM (108 kg)
customat <10° C
waitAfter 30 minutes
waitthe batch aged at 20° C. overnight
customThe phases were separated
washthe organic phase was washed with 5 wt % NaHCO3 (26 kg) and water (25 kg)
distillationThe organic phase was then distilled at atmospheric pressure to 30 L
additionEthanol (77 kg) was then added
additionfollowed by the addition of seed (10 g)
custom(Note: Crystallization
customtypically provides a more consistent product
customa better yield
distillation) The slurry was distilled in vacuo to a volume of 33 L
additionheptane (55 kg) was added dropwise
temperatureThe slurry was then cooled to 0° C.
filtrationfiltered
washwashed with 3:1 heptane
dry with materialethanol (30 L), and dried on the
filtrationfilter under nitrogen stream

Sources & evidence

ORD record: ord-a5bd0de5b4c8439f9b6442dd37ec79ac
Source dataset: uspto-grants-2013_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08487093B2

Reaction notes

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