Diltiazem enantiomers

Enzyme membrane reactor for production of diltiazem intermediate. A solution of the racemic ester in organic solvent enters the port at the bottom of the reactor and flows past the strands of microporous, hollow-fiber membrane that contain an enzyme. The enzyme catalyzes hydrolysis of one enantiomer of the ester that undergoes decarboxylation to 4-methoxyphenylacetaldehyde (which in turn forms a water-soluble bisulfite complex that remains in the aqueous phase). The other enantiomer of the ester remains in the aqueous stream that leaves the reactor via the port at the top. Courtesy of Sepracor, Inc. 

The obtained single enantiomer (-)-epox-ide (64) is then converted into the required (+)-isomer of Diltiazem (65) in several steps, as highlighted in Fig. 18.27. 

USA Patent No. 3,562,257 Germany Patent No. 1,805,714 Japan Patent No. 5,920,273 German Patent No. 3,415,035 and USA Patent No. 4,552,695. One approach (9) to stereospecific synthesis of diltiazem hydrochloride is shown in Figure 2. Diltiazem hydrochloride is prepared from (E)-methyl-4-methoxypropenoate ((1)] via either of the enantiomers of threo-methyl-3-(4-methoxyphenyl)-2,3-dihydroxypropanolate... 

Diltiazem hydrochloride possesses two asymmetric carbons and is therefore optically active. The dextrorotatory enantiomer is the more potent biologically active form (16, 17) and is, therefore, the form supplied. The optical rotation of a 1% (w/v)... 

Optical isomers of diltiazem hydrochloride may be separated by first derivatizing the isomers, followed by HPLC analysis. Diltiazem hydrochloride has two asymmetric carbon atoms. There are two geometric isomers, cis and trans, depending on the position of the substituents at these positions. Each isomer has optical isomers, the d- and I- forms. The enantiomers of diltiazem hydrochloride are separated by first hydrolysis to the desacetyl form followed by the introduction of a chiral species establishing diastereomers. The reaction is performed in the presence of pyridine. The diastereomers are separated using reversed-phase chromatography. The cis and trans isomers... 

Diltiazem is a calcium channel blocker used in the treatment of angina and hypertension. The active compound is the (+) enantiomer of the cE-diastereoisomer 57. The side chain (R = Me2NCH2CH2- in 57) can be added by alkylation of 58. The amide is an obvious disconnection. 

The diltiazem molecule ((3), R3 = OCOMe, R7 = H) has two chiral centres and it is also capable of cis-trans isomerism at these two carbon atoms. In general, the trans compounds do not cause vasodilation. Diltiazem is the dextrorotatory cis enantiomer. The laevorotatory cis enantiomer has a 10-fold longer duration of activity than diltiazem in increasing blood flow in the coronary sinus [75]. 

Figure 16.11 Chemical structure of the three most important representatives of the Cayl (L-type) channel organic antagonists DHPs (nifedipine), phenylalkylamines (verapamil), and benzothiazepines (diltiazem). The DHP derivative. Bay K8644, can be either agonist or antagonist depending on the optical enantiomer.

Asymmetric catalysis is not necessarily the cheapest method of making an enantiomer. Sometimes the number of steps involved in such a synthesis is so large that it becomes uneconomical (see Chapter 5). An example is the synthesis of diltiazem by asymmetric catalysis (Watson et al., 1990) which compares unfavorably with the enzymatic route. 

Bile salts are natural and chiral anionic surfactants which form helical micelles of reversed micelle conformation. The first report on enantiomer separation by MEKC using bile salts was the enantioseparation of dansylated DL-amino acids (Dns-o,L-AAs) and, since then, numerous papers have been available. Nonconjugated bile salts, such as sodium cholate (SC) and sodium deoxycholate (SDC), can be used at pH > 5, whereas taurine-conjugated forms, such as sodium taurocholate (STC) and sodium taurodeox-ycholate (STDC), can be used under more acidic conditions (i.e., pH > 3). Several enantiomers, such as diltiazem hydrochloride and related compounds, carboline derivatives, trimetoquinol and related compounds, binaphthyl derivatives, Dhs-dl-AAs, mephenytoin and its metabolites, and 3-hydroxy-l,4-benzodiazepins have been successfully separated by MEKC with bile salts. In general, STDC is considered as the the most effective chiral selector among the bile salts used in MEKC. 

The benzazepinone 59 was designed and tested as a more potent and a longer lasting analog of diltiazem, the benzothiazepinone calcium blocker of wide use in the treatment of hypertension and angina. Synthesis of 59 (Scheme 22) required the preparation of 58, which was prepared by microbial reduction of the dione 57. Due to the rapid equilibration of the latter compound, the reduction to one single enantiomer with microorganisms was possible. Thus compound 58 was obtained in optimized condition at 2 g/L in 96% yields and 99.9 e.e. with cultures of Nocardia salmonicolor [110]. 

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