Citalopram → 2-Hydroxymethyl-4-bromo-4'-fluorobenzophenone

HRID 2414461Notes

Reaction equation

HRID 2414461 reaction equation
CN(CCCC1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)OCC2C=C(C#N)C=CC1=2)C.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:31](=[O:32])[O:30][CH2:29]2.FC1C=CC(Br)=CC=1.[Mg]>CCOCC>[OH:30][CH2:29][C:28]1[CH:27]=[C:26]([Br:25])[CH:35]=[CH:34][C:33]=1[C:31]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:32]

Participants

6

Reactant 4

HCID 2771Citalopram2×HCID 99931-Bromo-4-fluorobenzeneHCID 6031445-Bromophthalide3×HCID 5462224Magnesium

Product 1

HCID 99226632-Hydroxymethyl-4-bromo-4'-fluorobenzophenone

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

The preparation of citalopram and its hydrobromide salt from 5-bromophthalide and the properties of such compounds was first reported in U.S. Pat. No. 4,136,193, which corresponds to German Offenlegungsschrift No. 2,657,013. U.S. Pat. No. 4,136,193 discloses a synthesis of citalopram starting from 5-bromophthalide, which involves the use of two successive Grignard reactions. In a first reaction, a Grignard reagent prepared from p-fluorobromobenzene and magnesium turnings in ether was reacted with 5-bromophthalide to give 2-hydroxymethyl-4-bromo-4′-fluorobenzophenone. The latter was isolated as a crude oil before, in a second reaction, being added to N,N-dimethylaminopropylymagnesium chloride to give (4-bromo-2-(hydroxymethyl)phenyl)-(4′-fluorophenyl)-(3-dimethylaminopropyl)-methanol. The latter was dehydrated with 60 aqueous phosphoric acid to yield 1-(4′-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalane, which was then refluxed with cupric cyanide in dimethylformamide to give citalopram.

Workup

  1. customIn a first reaction

Sources & evidence

ORD record
ord-cadd4e71058441c8984010d7c6a1a8a3
Source dataset
uspto-grants-2004_11
Patent number
US06812355B2

Reaction notes

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