Diltiazem, synthesis

Figure 1.51 Diltiazem synthesis using polyleucine epoxidation.

Also, in Andeno s diltiazem synthesis (Scheme 27), an early enantioselective enzymatic hydrolysis of an epoxy ester by a lipase is the key step, creating the necessary optically active intermediate 44 [106]. 

Production of an optically active diltiazem intermediate (2R, 3S)-methoxyophenylglyci-date methyl ester ((-)-MPGM) from racemic MPGM by the action of lipase from Serratia marcescens in a toluene aqueous biphasic system (Tanabe Seiyaku Co., Ltd.). For the continuous production of (-)-MPGM, a hollow fiber bioreactor was set up in collaboration with Sepracor Inc. The introduction of this enzymatic step allowed the shortening of the diltiazem synthesis from nine down to five steps. 

Kometani T, Sakai Y, Matsumae H, Shibatani X Matsuno R. Production of (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-l,5-benzothiazepin-4(5H)-one, a key intermediate for diltiazem synthesis, by bakers yeast-mediated reduction. /. Terment. Bioeng. 1997 84 195-199. 

Benzothiazepines belong to the three classes of calcium channel blockers which are important cardiovascular drugs in the management of angina pectoris and hypertension. A diastereoselective one-pot synthesis of the trans-and ds-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-l,5-benzothiazepin-4-one nucleus, a key intermediate in the preparation of the calcium channel blocker Diltiazem, was carried out under microwave irradiation in an open vessel (Scheme 25). Control of the diastereoselectivity was achieved by vary-... 

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. 

Diltiazem (19.3.10) The synthesis of this drag is described in Chapter 19. 

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... 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions.29 For example, baker s yeast reduction of (/ /5)-2-(4-methoxyphenyl)-l,5-benzothiazepin-3,4(2H,5H)-dione gave only (25, 35)-alcohol as a product out of four possible isomers as shown in Figure 28 (a).29a Only (5)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded enantioselectively. The resulting product was used for the synthesis of (25, 35)-Diltiazem, a coronary vasodilator. 

DM Floyd, RY Moquin, KS Atwal, SZ Ahmed, SH Spergel, JZ Gougoutas, MF Malley. Synthesis of benzazepinone and 3-methylbenzothiazepinone analogs of diltiazem. J Org Chem 55 5572-5575, 1990. 

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. 

The synthesis of calcium channel blockers of the diltiazem group, effective in lowering blood pressure, has been reported by Hoffmann-LaRoche (Scheme 23.6).51 A screening of several auxiliaries yielded acceptable ee, but it was found that the use of (7i ,2.S)-2-phenylcyclohcxanol (27) gave the required diastereoisomer 28 as the major isomer.52-54 The intermediate could be isolated readily, and the auxiliary could be recycled simply by base hydrolysis. Multi-kilogram quantities of enantiomerically pure naltiazem (29) and diltiazem (30) were produced by this method. 

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

Asymmetric Epoxidation of Electron-deficient trans-Olefins. (f )-l can also catalyze epoxidation of electron-deficient trans -olefins, especially ( )-cinnamate derivatives (eq 4). With 5 mol % of (f )-l, epoxidation of acrylate (5) is completed in 27 h with 74% yield and 85% ee. The crude product can be purified using a continuous dissolution and crystallization process to afford enantiomerically pure product and recover the ketone catalyst simultaneously. A similar practical method has been employed for large-scale synthesis of a key intermediate for diltiazem hydrochloride (a potent calcium antagonist for treatment of cardiovascular disease). 

Process options for the production of homochiral compounds are summarized in Fig. 2. The three basic routes are separation of racemic mixture, synthesis using a naturally occurring chiral synthon, and asymmetric synthesis using a prochiral intermediate. Historically, the efficiency of asymmetric synthesis has been capricious in terms of chemical and optical yield. Hence, from a practical, commercial process perspective, resolution via diastereomer crystallization has remained important for many commercial scale processes, for example, diltiazem. 

Figure 3 Synthesis of diltiazem using a chiral auxiliary.

Synthetic applications of AD which have already appeared and which are of potential industrial interest include the synthesis of propranolol (9) [48], diltiazem (10) [49], carnitine, and 4-amino-3-hydroxybutyric acid (11) [50], azole anti-fungals (12) [51], chloramphenicol (13) [52], reticuline intermediates (14) [53], camptothecin analogs (15) [54], khellactone (16) derivatives [55], taxol C-13 side chain (17) [56], halosarin [64], dehydro- xo-brevicomin [65], and antimalar-ial active cyclopenteno-l,2,4-trioxanes [57], as summarized in Figure 4. 

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