Malonic Acid → trans-3,4-Difluorocinnamic acid

HRID 130588Notes

Reaction equation

N1C=CC=CC=1.N1CCCCC1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])C=O>O>[F:20][C:21]1[CH:22]=[C:23](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:26]=[CH:27][C:28]=1[F:29]

Participants

Conditions

Temperature: 90 °C

Procedure

A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) were heated to 90° C. Malonic acid (17.6 kg) was added, followed by slow addition, over 50 minutes, of 3,4-difluorobenzaldehyde (12.0 kg). The reaction mixture was stirred at 90° C. for a further 4 hours and 36 minutes. Water (58.5 kg) was added and 32 litres of the pyridine/water mixture then was distilled out of the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) over a 40 minute period, then cooled to 25° C. with strong stirring. The solids were collected by filtration, washed twice with 1% hydrochloric acid (34.8 L per wash), once with water (61 L) and then deliquored thoroughly in the filter. The product was then dried under vacuum at 40° C. for 24 hours and 40 minutes, affording 13.7 kg of the crystalline product.

Workup

distillation32 litres of the pyridine/water mixture then was distilled out of the reactor under reduced pressure
waitThe reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) over a 40 minute period
temperaturecooled to 25° C. with strong stirring
filtrationThe solids were collected by filtration
washwashed twice with 1% hydrochloric acid (34.8 L per wash), once with water (61 L)
customThe product was then dried under vacuum at 40° C. for 24 hours and 40 minutes

Sources & evidence

ORD record: ord-1454926896d04a8da69e5e0aa1ac4151
Source dataset: uspto-grants-2008_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07381828B2

Reaction notes

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