1-Bromo-4-fluorobenzene → 4-[(4-Fluorophenyl)hydroxymethyl]-3-(hydroxymethyl)benzenecarbonitrile

HRID 2218539Notes

Reaction equation

HRID 2218539 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][CH2:6]2)#[N:2].BrC1C=C2C(=CC=1)C(=O)OC2.[F:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1.[Mg].[BH4-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.CC#N.O.CCOCC>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:10]=1[CH:8]([C:28]1[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=1)[OH:9])[C:1]#[N:2]

Participants

10

Reactant 6

HCID 99931-Bromo-4-fluorobenzeneHCID 6031445-BromophthalideHCID 8212181,3-Dihydro-1-oxoisobenzofuran-5-carbonitrile3×HCID 4311764Sodium borohydrideHCID 5462224MagnesiumHCID 21226445Aluminium lithium hydride

Product 1

HCID 99213624-[(4-Fluorophenyl)hydroxymethyl]-3-(hydroxymethyl)benzenecarbonitrile

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

In particular, step (a), consisting of the treatment of 5-cyanophthalide with a 4-fluorophenylmagnesium halide, occurs according to a classical Grignard reaction procedure, for example under the conditions described in Example 1 of U.S. Pat. No. 4,136,193 for the 5-bromophthalide, by treating 1.05-1.35 equivalents of a Grignard solution, titred at 15-20%, said solution being prepared from p-fluorobromobenzene and magnesium turnings in an ether, for example in tetrahydrofuran, with 5-cyanophthalide and by adding said Grignard reagent in the amount capable of consuming practically the whole starting 5-cyanophthalide. In practice, the operator controls the course of the reaction by HPLC [column: Develosil C18 4.6×250 mm, 5μ; DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aqueous NH4H2PO4+H3PO4 at pH=2.85/B: CH3CN/H2O=9/1 (v/v)] and stops it when 2-3% of unreacted 5-cyanophthalide remains. The product thus obtained is directly submitted to the next step (b) consinsting of a reduction with an agent reducing ketones to alcohols for example with NaBH4, or with LiAlH4 as described in Example 3 of U.S. Pat. No. 4,136,193, to obtain the corresponding 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile.

Workup

  1. additionby adding
  2. customof consuming practically the
  3. customthe course of the reaction by HPLC [column
  4. customThe product thus obtained

Sources & evidence

ORD record
ord-fa90730169fb4adf8b3d7f40cba2e82c
Source dataset
uspto-grants-2008_08
Patent number
US07411077B2

Reaction notes

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