Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
1999-05-17
2001-01-23
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
active
06177579
ABSTRACT:
The present invention relates to a process for the preparation of 13-cis-retinoic acid. Said compound, of formula I
is a medicament (also known as “isotretinoin”) with keratolytic activity, used particularly for the treatment of acne (see for further information, e.g. in “The Merck Index”, 11
th
Ed., page 1299).
A number of processes for the preparation of compound I are known. Thus, G. Paddenten et al. (J. Chem. Soc. 1968, 1984-1997) disclose its synthesis starting from a [3-methyl-5(2,6,6-trimethyl-1-cyclohenen 1-yl-2,4-pentadienyl]-triphenyl-phosphonium) halide which is condensed according to Wittig with 5-hydroxy-1-methyl-2(5-H)-furanone (=4-hydroxy-3-methyl-butenolide). Said process yields, however, a mixture of the desired product with 11,13-di-cis-retinoic acid (11) and 11,13-di-trans-retinoic acid (III) isomers
Therefore, compound (I), which is obtained in a markedly lower amount than (II) and in the smae amount as (III), has to be separated from the mixture by chromatography or fractional crystallization, with unsatisfactory yields.
EP 0 111 325 disclosed an improvement in the method by Paddenten, in which the Wittig condensation is carried out at tempertures ranging from −10 to −50° C., in alcoholic solvent and in the presence of alkali metal hydroxides, such as potassium hydroxide. A reaction product containing from 10 to 30% of the desired isomer (I) and from 70 to 90% of the isomer (II) is thereby obtained, with a conversion higher than 90% on the starting hydroxy-methyl-furanone. Said mixture, or the only isomer (II) separated therefrom, is subjected to isomerization in the presence of rhodium or palladium catalysts, to transform 11,13-di-cis-retinoic acid into the desired 13-cis-retinoic acid.
Said process, which provides 13-cis-retinoic acid in yields higher than those according to Paddenten, has however a drawback in that the isomerization of 11,13 di-cis-retionic acid involves the use of metals, such as rhodium and palladium, which are not only very expensive, but also difficult to separate from 13-ciis-retinoic acid. Furthermore, the presence of traces of said metal (or, more generally, of heavy metals) in 13-cis-retinoic acid, is not only in contrast with the required purity criteria, but also is a factor contributing to the known instability of the product (evidenced, inter alia, by X. Tan et al. in
Pharmaceutical Res.
1992, (9), 1203-1208).
Palladium traces can also remain (and usually remain, unless a thorough purification is carried out, which is economically unacceptable) when operating according to the process claimed in DPR 1,059,900 and DPR 1,068,702 (and described by P. S. Manchard et al.,
J. Chem. Soc.,
1965, 2019) for the synthesis of retinoids starting from vinyl-beta-ionol. Said intermediate has, in fact, been obtained from beta-ionone by reaction with acetylene (
J. Amer. Chem. Soc.,
71, 2062 (1949) and subsequent reduction of the triplebond on a partially poisoned palladium catalyst.
Furthermore, DE 4,314,089 discloses a process for the preparation of 13-cis-retinoic acid in which the reaction between 4-hydroxy-3-methyl-butenolide and [3-methyl 5 (2,6,6-trimethyl-1-cyclohenen-1-yl)-2,4 pentadienyltriarylphosphonium salt is carried out in the presence of lithium hydroxide and dimethylformamide at temperatures ranging from 10 to 9° C., to give a mixture of 13-cis-retinoic and 11,13-di-cis-retinoic acids lithium salts, which are subsequently converted into the respective acids, by treatment with sulfuric acid. The resulting mixture is solubilised in alcoholic solvent and subjected to photochemical isomerization to obtain 13-cis-retinoic acid.
This process is a remarkable improvement compared with the prior art, in that the isomerization requires no use of said catalysts, but it also has a series of drawbacks, as the photochemical isomerization is carried out on the mixture of retinoic acids which are per se poorly soluble in the reaction solvents compatible with said photochemical isomerization: as a matter of fact, solutions containing the above mentioned mixture of acids in concentrations below 10% have to be used.
On an industrial scale, the process therefore requires remarkable amounts of solvents, to the detriment of the economy of the process as well as the safety of the workers.
Furthermore, such mixture of acids is rather unstable in said organix solvents, also due to traces of palladium from vinyl-beta-ionol (IV).
Said drawbacks have partially been overcome by the Italian Patent application MI 94 A 002752 in the Applicant's name, in which photoisomerization is carried out on the aqueous solution of a 11,13-di-cis-retinoic acid alkali salt. However, this process also involves the drawback due to the presence of palladium traces.
It has now been found a novel process which provides 13-cis-retionoic acid in a highly stable and pure state, thanks to a synthetic pathway which avoids at any step the use of palladium or other heavy metals. Said synthesis combines the advantages of photochemical isomerization on the 11,13-di-cis-retinoic acid alkali salt (or on alkali salts of the mixture of acids from the preceding Wittig condensation) by use of vinyl-beta-ionol (IV) obtained according to the invention—from beta-ionone and a vinyl magnesium halide.
The process according to the invention can be summarized as follows.
A) beta-ionone (IV) is reacted with a vinyl magnesium halide (V) (chloride, iodide or—preferably—bromide):
B) resulting vinyl-beta-ionol (VI) is subjected to Wittig condensation with 4-hydroxy-3-methyl butenolide (VII) according to the process by Paddenten (see above) or to that disclosed in EP 115,325, the reaction product consisting of a mixture of 13-cis-retinoic acid (I), 11,13-di-cis-retinoic acid (II) and 11,13-di-trans-retinoic acid (III):
C) the alkali metal salts of the resulting mixture of the three acids, dissolved in water, are subjected to photochemical isomerization in aqueous solution, to give 13-cis-retinoic acid (I) with high purity and stability.
Step A) of the process of the invention is carried out under Grignard reaction conditions (well known to those skilled in the art), at tempertures ranging from −40° C. to +50° C., preferably from −15° C. to −30° C. A preferred solvent is tetrahydrofuran, but other ethers may also be used. The vinyl magnesium halide used is preferably the bromide. At the end of the reaction, product (VI) is recovered with conventional techniques.
Step B), as already mentioned, can be carried out following the conventional procedure by Paddenten or the modified disclosed in EP 115,325.
The operative details of step C) are those claimed in the already cited Italian Patent application (MI96A-002752) in the Applicant's name, with the advantages—compared with the prior art—disclosed in said application, and can be summarized as follows: higher stability of (I) alkali salts in aqueous solution compared with thee free acid in organic solvents; higher reaction rate; higher economy and, above all, lower risks on an industrial scale; operative advantages deriving from the use of solution of nearly triple concentration compared with those used with organic solvents.
The following examples further illustrate the process according to the invention.
REFERENCES:
patent: 3200231 (1983-07-01), None
patent: 4313089 (1994-10-01), None
patent: 0850925 (1998-07-01), None
R.W. Curley Jr.: J. Org. Chem., vol. 49, No. 11, 1984 pp 1941-1944.
G. Pattenden Et Al: J. Chem Soc. (C), 1968 pp 1984-1997.
Bucknam and Archer
Carr Deborah D.
Laboratori Mag S.p.A.
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