Diltiazem intermediate

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. 

In spite of the clear advantages, membrane-coupled processes often turn out to be still more expensive, because of the costs of membrane and all additional hardware associated with a membrane operation. Membrane separations tend to become more favorable for processes where the selectivity is more important than the conversion, because it replaces other purification steps that might lower such selectivities, like in the production of the chiral diltiazem intermediate. Membrane fouling, mass transfer limitations, biocatalyst activity loss, and biocatalyst denaturation are other potential disadvantages related to it. 

Figure 7-37. Membrane reactor system for resolution of a diltiazem intermediate.

T. Shibatani, K. Omori, H. Akatsuka, E. Kawai, H. Matsumae, Enzymatic resolution of diltiazem intermediate by Serratia marcescens lipase molecular mechanism of lipase secretion and its industrial application J. Mol. Cat. B. Enz. 2000, 10,141-149. 

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. 

Scheme 51 Transfer hydrogenation for a diltiazem intermediate (Avecia/Piramal)...

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-... 

The pharmacological activity of the 1,5-benzothiazepine derivative diltiazem has given further impetus for synthetic routes to this ring system. A traditional preparation of the intermediate 62 by the reaction sequence shown in Scheme 12 has been subject to microwave studies, when the final product was obtained as a mixture of isomers <96TL6413>. Under optimised conditions irradiation in toluene at 390 watts for 20 minutes gave mainly the cis-isomer as the main product (cis/trans 9 1) in 75% yield. However, reaction at 490 watts in the presence of acetic acid resulted in a reversal of this ratio and a yield of 84%. The... 

Ca++-channel blockers. Verapamil has powerful effects on the heart, decreasing heart rate and myocardial contractility ( l CO) and causing some vasodilation. On the other hand, nifedipine is a more potent vasodilator (1 TPR) with weaker myocardial effects. The effects of diltiazem are somewhat intermediate, in that this drug has moderate inhibitory effects on the myocardium and vascular smooth muscle. 

An example of an industrial membrane bioreactor is the hollow-fiber membrane system for the production of (-)-MPGM (3-(4-methoxyphenyl)glycidic acid methyl ester), which is an important intermediate for the production of diltiazem hydrochloride [81, 82]. For the enantiospecific hydrolysis of MPGM a hollow-fiber ultrafiltration membrane with immobilized lipase from Serratia marcescens is used. (-f)-MPGM is selectively converted into (2S,3J )-(-F)-3-(4-methoxyphenyl)glyci-dic acid and methanol. The reactant is dissolved in toluene, whereas the hydrophilic product is removed via the aqueous phase at the permeate side of the membrane, see Fig. 13.9. EnantiomericaUy pure (-)-MPGM is obtained from the to-... 

A method based on the use of PPL has been commercialised by DSM-Andeno and also other companies. Another mannfactnring process involving an epoxide intermediate is the lipase-catalysed resolution of the methyl ester of p-methoxyphenylglycidate, which is an intermediate in the process of Diltiazem, a cardiovascular dmg. 

J.L. Lopez and S.L. Matson, A Multiphase/Extractive Enzyme Membrane Reactor for Production of Diltiazem Chiral Intermediate, J. Membr. Sci. 125, 189 (1997). 

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. 

Membrane bioreactors have been reported for the production of diltiazem chiral intermediate with a multiphase/extractive enzyme membrane reactor [15, 16]. The reaction was carried out in a two-separate phase reactor. Here, the membrane had the double role of confining the enzyme and keeping the two phases in contact while maintaining them in two different compartments. This is the case of the multiphase/ extractive membrane reactor developed on a productive scale for the production of a chiral intermediate of diltiazem ((2R,3S)-methylmethoxyphenylglycidate), a drug used in the treatment of hypertension and angina [15]. The principle is illustrated in... 

Production of aspartame (Industrial scale) [14] Production of diltiazem chiral intermediate (industrial scale) [15, 16]... 

Lopez, J.L. and Matson, S.L. (1997) A multiphase/extractive enzyme membrane reactor for production of diltiazem chiral intermediate. Journal of Membrane Science, 125, 189. 

Figure 3 MIC formation by diltiazem (5 pM) in HLMs. The sample cuvette contained HLMs, diltiazem, and NADPH, whereas the reference cuvette contained HLMs, buffer, and NADPH. The ribbons represent the change in absorbance difference for scans from 5 to 120 minutes. Abbreviations MIC, metabolic intermediate complex HLMs, human liver microsomes. Source From Ref. 37.

Jones DR, Gorski JC, Hamman MA, et al. Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation. J Pharmacol Exp Ther 1999 290(3) 1116-1125. 

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. 

Verapamil [ver AP a mill] shows greater action on the heart than on vascular smooth muscle, whereas nifedipine, a calcium channel-blocker used to treat hypertension (see p. 187) exerts a stronger effect on vascular smooth muscle than on the heart. Diltiazem [dil TYE a zem] is intermediate in its actions. 

In the case of biocatalysis, enzymes [3] and catalytic antibodies [4] have attracted most attention. Since enzymes are inherently the more active catalysts, they have been used most often. Indeed, many industrial processes for the enantioselective production of certain chiral intermediates are based on the application of enzymes, as in the lipase-catalyzed kinetic resolution of an epoxy-ester used in the production of the anti-hypertensive therapeutic Diltiazem [5]. Recently, it has been noted that there seems to be a trend in industry to use enzymes more often than in the past... 

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). 

Chemists in Japan have developed an excellent approach to (+)-Diltiazem, which is a coronary vasodilator (108). An intermediate... 

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. 

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]. 

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. 

Diltiazem hydrochloride and its related compounds can be separated in both bulk drug and finished tablets using a Waters pBondapak C18 column (10 pm particle size, 300 mm x 3.9 mm I.D.) and a mobile phase of buffer methanol acetonitrile (50 25 25, v/v) at a flow rate of about 1.6 mL/minute. The buffer is 0.1 M aqueous sodium acetate containing 5mM d-camphorsulfonic acid (99%) adjusted to pH 6.2 with 0.1 M aqueous sodium hydroxide. Detection of the compounds is achieved using UV absorbance at 240 nm. The method provides for the resolution of trans-diltiazem and seven known and unidentified related compounds. Diltiazem hydrochloride elutes at approximately 21 minutes under these conditions. The minimum detectable amounts are less than 0.1% for all related compounds except for one of the synthetic intermediates for which there is a limit of about 2% (27). 

Lipases can hydrolyze triglycerides into fatty acids and glycerol. They have been used extensively to produce optically active alcohols, acids, esters, and lactones by kinetic resolution. Lipases are unique, in that they are usually used in two-phase systems. A classic example is the use of a lipase for the production of (5, / )-2,3-p-methoxyphenylglycyclic acid, an intermediate for diltiazem. In this process, methyl-/7-methoxyphenylglycidate is stereospecifically hydrolyzed by a lipase immobilized in a hollow fiber membrane reactor. The enzyme is located at the interfacial layer between an organic and an aqueous phase. 

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