Methyl formate → Methyl 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylate

HRID 2040928Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:20](OC)=[O:21].CC(C)([O-])C.[K+]>>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:20][OH:21]

Participants

Reactant 3

HCID 7865Methyl formate

HCID 23665647Potassium tert-butoxide

HCID 59800203Methyl 2-(5-chloro-2-phenoxyphenyl)acetate

Product 1

HCID 66859650Methyl 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylate

Procedure

Example 8 of the European Patent EP 1710241 B1 also describes an alternative process for the synthesis of the lactam (VI), see Scheme 4. In this example, (5-chloro-2-phenoxyphenyl)acetic acid methyl ester (compound VIIIa) is reacted with methyl formate in the presence of potassium tert-butoxide to give 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylic acid methyl ester (compound IXa, E/Z mixture 9:1), which is directly cyclized with pyrophosphoric acid to obtain methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa), referred to us 8-chlorodibenzo[b,f]oxepin-10-carboxylic acid methyl ester in EP 1710241 B1, with 85% yield. This compound is then reacted with nitromethane in the presence of tert-butyl-tetramethylguanidine to give methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), referred to us 8-chloro-1′-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, with a trans to cis ratio of 8:1, which is directly hydrogenated in the presence of a sponge nickel catalyst to give methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), referred to us 11-aminomethyl-8-chloro-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, which after treatment with potassium tert-butoxide and dimethyl sulphate, is converted into the lactam (VIa) with an overall yield of 81% from compound (Xa), but predominantly corresponding to the undesired cis-isomer (approximately 85:15 ratio with respect to the trans-isomer), being therefore necessary to carry out one of the above described low-yield processes for the conversion of undesired cis-(VI) to trans-(VI).

Sources & evidence

ORD record: ord-615c0c14c121444abc34084f2c691644
Source dataset: uspto-grants-2013_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08580972B2

Reaction notes

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