Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1993-06-23
1995-01-17
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D28110
Patent
active
053826639
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to an improved process for the preparation of (+)-cis-3-(acetoxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-2-(4-methoxyph enyl)-1,5-benzothiazepin-4(5H) -one hydrochloride of formula (I): ##STR1##
This compound, also known under the International Common Denomination of "Diltiazem", is of paramount practical importance for its important pharmacological activities.
The literature discloses several processes for preparation of compound (I). Particularly U.S. Pat. No. 3,562,257 discloses a synthesis of (I) which includes the following steps: one (II): ##STR2## obtained as disclosed in the same U.S. Pat. No. 3,562,257, is reacted with dimenhylaminoethyl chloride of formula (III): ##STR3## which is subsequently transformed by acetylation into the final product (I). The above mentioned U.S. Pat. No. 3,562,257 claims the following conditions for the main step, i.e. for the reaction between (II) and (III): reaction of (II) with sodium hydride, metallic sodium or sodium amide in a solvent such as dimethyl sulfoxide, dioxane, toluene or xylene, and subsequent reaction of the obtained salt with (III). Sodium hydride and dimethyl sulfoxide are respectively the preferred base and solvent. The process is unsatisfying from the safety point of view (as it is well known, the mixture NaH/(CH.sub.3).sub.2 SO may give rise to explosions) and under ecological aspects; it requires long times and produces large amounts of waste sewage which must be incinerated to avoid pollutions. These drawbacks have only partially been overcome by subsequently disclosed processes. For example, U.S. Pat. No. 4,438,035 (corresponding to EP 0,081,234) discloses a process to obtain compound (I), which is carried out according to the scheme reported in U.S. Pat. No. 3,562,257, but the reaction between (II) and (III) is effected using potassium carbonate in a solvent selected from acetone, a lower alkyl acetate or an acetone/water mixture. Acetone and acetone/water are preferred solvents; as tests from the applicant have demonstrated, acetone alone fits badly to this reaction, because long reaction times, up to two days, are needed to obtain good yields. Good yields are obtained with acetone/water in shorter times. A drawback of this process resides in its high ecological cost. In fact at the end of the reaction solvent must be removed and incinerated, with high costs, since it is contaminated by compound (III) and by-products and cannot by recycled.
Another drawback resides in operating in solid-liquid eterogeneous phase, with problems connected with the stirring of the reaction mixture and especially with the necessity to eliminate the salts (KCl and unreacted K.sub.2 CO.sub.3) at the end of the reaction.
This must be accomplished with a centrifugation which requires long times, due to the physical form of the solid. The final step (the transformation of (IV) into (I)) entails acetone evaporation, redissolution in toluene and acetylation with acetic anhydride.
Finally, EP-A-158,303 discloses a process according to which the reaction between the intermediate (II) and the reagent (III) is carried out under phase-transfer conditions. Typically, an halogenated organic solvent, such as methylene chloride, chloroform or 1,2-dichloroethane, is used, optionally at the presence of a catalyst, such as a quaternary ammonium halide. Calcium or barium hydroxide in aqueous phase are normally used as halohydric acid acceptors. At the end of the reaction the solvent is evaporated and the residue is taken up in toluene for the acetylation reaction.
The drawback of this process resides especially in using a highly polluting solvent which is also of difficult elimination. It is well-known, in fact, that halocarbons always show severe problems when they must be eliminated by incineration. In this case, as the tests of Applicants demonstrate, the solvent coming from the reaction is so polluted that its recovery is not economical, therefore it is destroyed.
A further drawback consists of the necessity to change the solvent before the acetyla
REFERENCES:
patent: 4902684 (1990-02-01), Floyd
patent: 4937334 (1990-06-01), Cavicchioli
Koziara, Synthesis 527 (1979).
Hampl, Chem Abs. 114, 207024d (1991).
Manghisi Elso
Perego Bruno
Berch Mark L.
Lusochimica S.p.A.
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