Synthesis of Diltiazem

The calcium antagonist diltiazem 26, which is one of the top 20 selling drugs world-wide according to a 1990 estimate [39], is currently commercialized as a single (S,S)-stereoisomer. While early synthesis developed by Tanabe Seiyakii Co. involved classical resolution of an advanced precursor, a more recent process employed by Andeno [39] exploits an early enzymatic resolution of an a,(3-epoxyester. 

The unavoidable loss of 50% of material intrinsic in both these routes, clearly called for the development of stereoselective syntheses of diltiazem. One of these [52] is based on the use of an oxazolidinone as chiral auxiliary, and is reported in Fig. 13. 

A-Acyloxazolidinone 23 was condensed with p-anisaldehyde to give, after dehydration, the Michael acceptor 24, mainly in the shown (Z) form. Addition of the 5-lithium salt of 2-amino-thiophenol afforded an 82 18 mixture of 2,3-syn and -anti adducts 25. From the major isomer, diltiazem was obtained upon ring closure, MEM group removal, hydroxy group acetylation, and nitrogen alkylation. 

Far from being industrially viable, this synthesis showed that a chiral auxiliary-based approach to the drug was possible, and very recently an alternative and much more attractive route has been reported by DSM [53]. This is described in Fig. 14. 

The a-chloroacetic acid ester of the readily available (lS,2f )-l-A ,A-dimethylaminoinda-nol 27 was reacted with potassium t-butoxide and p-anisaldehyde to give the Darzens condensation product 28 as an 89 11 mixture of diastereoisomeric epoxides. The one reported in the figure is the major component of the mixture and has the required (2R,3S) configuration. Treatment with 2-amino-thiophenol at 120 °C led to adduct 29 from which 26 was eventually obtained by known procedures. 

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Choudary, B.M., Chowdari, N.S., Mahdi, S., Kantam, M.L. (2003) A Trifimctional Catalyst for One-Pot Synthesis of Chiral Diols via Heck Coupling-N-Oxidation-Asymmetric Dihydroxyla-tion Application for the Synthesis of Diltiazem and Taxol Side Chain. Journal of Organic Chemistry, 6S, 1736-1746. 

Adger, B.M., Barkley, J V. Bergeron, S., Cappi, M.W., Elowerdew, B.E., Jackson, M. R, McCague, R., Nugent, T.C. and Roberts, S.M. Improved Procedure for Julia-Colonna Asymmetric Epoxidation of a,/l-Unsaturated Ketones Total Synthesis of Diltiazem and Taxol Side-chain. J. Chem. Soc., Perkin Trans. 1 1997, 23, 3501-3507. 

In a new synthesis of diltiazem (98b R = Ac, X = CH2CH2NMe2), a calcium antagonist used in the treatment of hypertension, the key step is the diastereoselective reduction of a-ketolactam (97) to the alcohol precursor (98a R = X = H).158 The reduction of the 1,5-benzothiazepine (97) was achieved using an NaBH4-(,S )-amino acid combination (,S )-/-lcucinc was most efficient, and was readily recovered unracemized. 

HOLLOW-FIBER MEMBRANE REACTOR FOR THE LIPASE CATALYZED HYDROLYSIS SYNTHESIS OF DILTIAZEM... 

H Matsumae, M Furui, T Sabatani. Lipase-catalyzed asymmetric hydrolysis of 3-phenylglycidic acid ester, the key intermediate in the synthesis of diltiazem hydrochloride. J Ferment Bioeng 75 93-98, 1993. 

Scheme 12.15 Polyleucine-mediated epoxidation in the synthesis of diltiazem 30.

Figure 3 Synthesis of diltiazem using a chiral auxiliary.

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... 

Figure 2. An example of a stereospecific synthesis of diltiazem hydrochloride.

Fig. 1. Enzymatic kinetic resolution of an intermediate used in the synthesis of Diltiazem...

Asymmetric Induction at the Allylic Alcohol Centre AE is anti-Selective No Asymmetric Induction from Remote Allylic Alcohol Centre Reagent Control Asymmetric Synthesis of Diltiazem Summary of Sharpless Epoxidation... 

Electron-donating groups on the benzene ring improve the cis.trans ratio and isopropyl esters improve the ee. This make for a simple synthesis of diltiazem 62 a compound we have already made by AE and AD. Epoxidation of 213 gives a reasonable yield of nearly enantiomerically pure ds-epoxide 214 (only 10% of the trans epoxide is formed). 

Industrial Synthesis of Diltiazem via Chiral Catalysis (Scheme 48)... 

Trans-(2R,3S)-(4-methoxyphenyl)glycidic acid methyl ester is an intermediate in the synthesis of diltiazem, a coronary vasodilator and a calcium channel blocker with... 

Figure 13. Stereoselective synthesis of diltiazem. Reagents a, LDA, 4-MeOQiH4CHO b, MsCI, TEA c, DBU d, 2-(lithiomercapto)aniline e, Me3Al f, TiCl4 g, Ac20 h, alkylation.

The stereoselective synthesis of epoxide 28 appears to be the major advantage of this route, since it generates an intermediate already involved in an industrial synthesis of diltiazem. The recent development of basic research methods for the catalytic enantioselective epoxidation of electron poor alkenes [54] can provide a new entry to 26 that is more practical than the approaches of both DSM and others [55]. 

These parameters were probed in an in-depth study dealing with the epoxidation of cis-cinnamate esters 11, a protocol Jacobsen has used for the enantioselective synthesis of diltiazem (13), a commercial anti-hypertensive agent [94TET4323]. Surprisingly, electronic and steric factors on the phenyl moiety exercise practically no influence on the enantioselectivity (1st step) of the reaction, whereas increasing steric... 

Lipases used in laundry detergents and in other bulk applications do not require enzyme immobilization however, an increasing number of applications in synthesis and biotransformation demand an immobilized biocatalyst for efficient use. It has been claimed that the success of a lipase catalyzed biotransformation for the production of certain pharmaceuticals depends on immobilization. For example, in the industrial preparation of the chiral intermediate used in the synthesis of Diltiazem, the lipase from Serratia marcescens was supported in a spongy matrix, which was used in a two-phase membrane bioreactor (Cowan 1996). 

A particularly important application is in the synthesis of diltiazem, for which two routes have been proposed. The original route developed by Tanabe (see Sheldon, 1996) involving late resolution via diastereomeric salt crystallization... 

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. 

Adger BM, Barkley JV, Bergenm S, Cappi MW, Flowerdew BE, Jackson MP, McCague R, Nugent TC, Roberts SM (1997) Improved Procedure for Julia-Colonna Asymmetric Epoxidation of a,P-Unsaturated Ketraies Total Synthesis of Diltiazem and Taxol (TM) Side-Chain. J. Chem Soc Perkin Trans I 3501... 

These enantiomerically enriched a-chloro- -hydroxyesters were used to synthesise optically active glycidates, such as (2i ,35)-3-(4-methoxyphenyl) glycidate, a key intermediate for the synthesis of diltiazem, a potent calcium channel blocker used for the treatment of hypertension (Scheme 2.8). " The preparation of tram (25,3i )-methyl-3-phenylglycidate under similar conditions provided an efficient route to the taxotere side chain, as shown in Scheme 2.8. 

Methyl 2,3 epoxy 3-(4-methoxyphenyl)propionate is an intermediate product in the synthesis of diltiazem hydrochloride. Contact dermatitis was observed in several laboratory technicians. 

The versatility of asymmetric organocatalysis was demonstrated by the practical synthesis of methyl (27, 35)-3-(4-methoxyphenyl)glycidate, a key intermediate in the synthesis of diltiazem. Therefore, the key step of this synthesis was the asymmetric epoxidation of methyl ( )-4-methoxyeiimamate using a chiral dioxirane generated from Yang s catalyst. This reaction provided the desired epoxide in high chemical and optical yields, as shown in Scheme 7.8. 

This procedure has been applied to the preparation of a key intermediate in the industrial synthesis of diltiazem, a drug used to treat hypertension, angina, and arrythmia. In this case, the racemic reactant is a methyl ester, and lipase-catalyzed hydrolysis selectively... 

Hollow-fiber membrane reactor for lipase-catalyzed hydrolysis synthesis of diltiazem... 

We emphasize that the majority of the above suggestions are not presented in literature devoted to the synthesis of Diltiazem. This may be simply understood since the preparations and manipulations of kete-nes and isocyanates belong to a very awkward part of preparative organic chemistry. 

Ketone 54 has been applied by scientists at Tanabe Seiyaku Company (Osaka, Japan) in the large-scale preparation of chiral epoxide 59, an important intermediate in the synthesis of diltiazem (Scheme 35.15). Treatment of olefin... 

SCHEME 35.15. The asymmetric epoxidation with C2-symmetric chiral hinaphthyl ketone 54 for the synthesis of diltiazem. 

A chiral intermediate (2R,iiS)-3-(4-methoxyphenyl)glycidic acid methyl ester [(—)-MPGM] 76 is required for the synthesis of diltiazem 72, a calcium channel antagonist. Matsumae et al. [Ill] screened over 700 microorganisms and identified lipase from Ser-... 

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