Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1987-03-06
1989-12-05
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
570128, 585400, 548444, 548445, 549 12, 549 14, 549 35, 549 39, 549 72, 549 78, 549369, 549370, 549430, 549448, 562418, 562 41, 568 58, 568592, 568632, C07C 47796, C07C 43243
Patent
active
048854042
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
A number of processes to produce flurbiprofen are known, see for example, U.S. Pat. Nos. 3,959,364, 4,188,491 and 4,443,631.
The halo (I) starting materials are known, see U.S. Pat. No. 3,959,364 (column 8, lines 56-61); U.S. Pat. No. 3,959,364 (Example 9); U.S. Pat. No. 3,663,584 and Aldrich Catalog; Japanese Pat. No. 56,097,249 and Dutch Pat. No. 6,810,246 for (IA) thru (IE) respectively. The halo starting material (IF) can be prepared by methods well known to those skilled in the art. Aromatic olefins similar to the olefin (II) are known, see U.S. Pat. No. 4,036,989, more particularly Table III, Example No. 15. While that compound is isomeric with (IIA), if subjected to ozonolysis it will not produce the desired aldehyde (IIIA). Other aromatic olefins are disclosed in German Offen. 2,259,243 and Japanese Pat. No. 53,046,943. British Pat. No. 1,586,798 generically discloses the olefin (IIA); however, none of the sixteen examples sets forth any of the six olefins (IIA-IIF) of the present invention.
The aldehyde (IIIA) is known, see Japanese Pat. Nos. 55,127,336, 53,046,943 and Swedish Pat. No. 7,406,883.
The conversion of a halo compound to an aromatic Grignard reagent and its reaction with an unsaturated allylic halide is discussed in J. Org. Chem. 36, 2099 (1971), ibid 33, 2148 (1968) as well as U.S. Pat. No. 4,036,989. Prior art yields are about 75% whereas the yields of the present invention are 95 to 99%.
The ozonolysis of alkenes to the corresponding aldehydes is well known. British Pat. No. 1,586,798 discloses methods of oxidizing aromatic olefins to the corresponding acids. The British Patent discloses various oxidizing agents including ozone, and state the yield is very good.
The oxidation of an aldehyde to the corresponding acid is well known. In the present case the process is complicated by the benzylic proton which is subject to loss by over-oxidation thereby reducing the yield. Acta Chem. Scand. 27, 888 (1973) discloses the oxidation of aldehydes to acids using sodium chlorite and the requirement for a chlorine scavenger. British Pat. No. 1,445,283 describes the oxidation of biaryl aldehydes to the corresponding acids. See page 11, column 2 for the aldehyde XXXI. However, the British Patent uses standard oxidizing agents; see page 7 where various oxidizing agents are used but no mention is made of chlorite. British Pat. No. 1,549,140 discloses a process for oxidation of aromatic aldehydes to the corresponding acids by use of aqueous chlorite. However, no buffer was used, and the yields were only about 66 to about 76.5%. East German Pat. No. 118,605 discloses chlorite oxidation of 2-(4-isobutylphenyl)propionaldehyde to ibuprofen at very low pH and in only 62% yield. Japanese Kokai 53018534 discloses hypochlorite (not chlorite) oxidation of 2-(4-isobutylphenyl)propionaldehyde to ibuprofen in 82% yield without regulation of the pH. Romanian Pat. No. 79,333 discloses aqueous chlorite oxidation of 2-(4-isobutylphenyl)propionaldehyde in the presence of a chlorine scavenger to give ibuprofen in 85-90% yield. Afinidad, 384, 142-3 (1983) discloses the production of naproxen from the corresponding naproxen aldehyde by unbuffered chlorite oxidation. The process of the present invention requires a chlorine scavenger and that the pH be maintained in the range of about 4 to about 7 providing yields>90%.
SUMMARY OF THE INVENTION
Disclosed is an olefin (II) and a bisulfite adduct (VI).
Also disclosed is a process for the preparation of the olefin (II) which comprises contacting an organometallic compound (G) with an allyl halide (V) where the allyl halide (V) and the organometallic compound (G) are contacted slowly over the period of at least 30 min.
Further disclosed is a process for the preparation of an aldehyde (III) which comprises contacting an olefin (II) with ozone in the presence of a trapping agent at a temperature of about -70.degree. to about 10.degree..
Additionally disclosed is a process for the preparation of an acid (IV) in >90% chemical yield which comp
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patent: 3959364 (1976-05-01), Armitage
patent: 4036989 (1977-07-01), Armitage
patent: 4188491 (1980-02-01), Nicholson
patent: 4443631 (1984-04-01), Padilla
patent: 4549025 (1985-10-01), Dalcanale
J. Org. Chem., 36, 2099 (1971), Ronald M. Magid et al., "The Coupling Reaction of Phenyllithium with Allylic Chlorides . . . ".
J. Org. Chem., 33, 2148 (1968), R. G. Gough et al., "Radical Mechanisms in Reactions of Grignard Reagents".
Acta Chem. Scand., 27, 888 (1973), B. O. Lindgren et al., "Preparation of Carboxylic Acids from Aldehydes . . . ".
Afinidad 40, 384 (1983).
Raymond Richard L.
Stein Bruce
The Upjohn Company
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