Resolutions Diltiazem

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. 

For example, in the optical resolution of diltiazem, a benzothiazepin derivative, with optically active mandelic acid, one of the diastereomeric salts with the same stereochemical sign (+) (+) or (-) (-) is crystallized from ethyl acetate whereas another with the opposite stereochemical sign (+) ( ) or (-) (+) is obtained from a mixed solvent of ethyl acetate and benzene (1 1).21 In the resolution of 1-phenyl-2-(p-tolyl)ethylamine with the same chiral acid, the same sign salt crystallizes from 50 % aqueous methanol and the opposite one from 2-propanol.22... 

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. 

Diltiazem Bulk HPLC Derivatize with S (-)/V- Silica methanol (1% ammonium hydroxide) (4 1) Methylene chloride- 254 nm [2.9] Resolution of [973]... 

K. Shimizu, T. Kakimoto, K. Ishi, Y. Fujimoto, H. Nishi, and N. Tsumagari, New derivatization reagent for the resolution of optical isomers in diltiazem hydrochloride by high-performance liquid chromatography, J. Chromotogr., 357 119 (1986). 

Procedure Inject 20 pL of each solution. Continue the chromatography of Solution (1) for at least nine times the retention time of dipyridamole. This test is not valid unless in the chromatogram obtained with Solution (3), the resolution factor between the peaks due to diltiazem and dipyridamole is at least 2. 

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... 

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. 

In this case, the self-limiting resolution in 4-5 days without relapse, the presence of the skin rash, and the liver sequelae suggested a common immunoallergic mechanism. The clinical symptoms, the time relation between drug administration and the occurrence of the syndrome, the inability to explain the syndrome otherwise, and its disappearance on withdrawal of diltiazem support an association with the drug. 

The infrared spectrum of diltiazem hydrochloride dispersed in potassium bromide was recorded at 4 cm 1 resolution on a Nicolet Model 740 FTIR (11). Figure 3 shows the diltiazem HCI vibrational features in the 4000 to 400 cm-1 region after spectral subtraction of the absorptions (3430 and 1629 cm 1) due to adsorbed water. Table I lists characteristic frequencies, relative intensities, and vibrational assignments for the primary diltiazem HCI absorption bands. 

The low resolution mass spectrum of diltiazem HCI shown in Figure 7 was obtained using a Finnigan 4500 mass spectrometer operated at 70 eV in the direct probe electron impact mode (15). The molecular ion of the free base is seen at m/z = 414 and the protonated free base ion is observed at m/z = 415. The fragmentation pattern (Figure 8) is consistent with the chemical struture. 

Figure 7. Low resolution mass spectrum of diltiazem hydrochloride.

The infrared spectrum of diltiazem hydrochloride is obtained from a potassium bromide disc and is recorded at 4 cm 1 resolution. A disc is made from 1 mg of sample in about... 

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. 

The types of enzymes used by organic chemists vary widely and include such well-known biocataiysts as lipases, esterases, oxidoreductases, oxinitrilases, transferases and aldolases [4]. An example which illustrates the industrial application of a lipase concerns the kinetic resolution of a chiral epoxy ester used as the key intermediate in the synthesis of the calcium antagonist Diltiazem, a major therapeutic in the treatment of high blood pressure [6] (Fig. 1). In developing the industrial process for the production of this drug, many different lipases were screened, but only the bacterial lipase from Serratia marescens showed both a sufficiently high activity and enantioselectivity. The intermediate is produced industrially on a scale of 50 tons/year. 

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

An immobilized lipase, from M. miehei, was used by Aaltonen s group for the kinetic resolution of tra w-3-(4-methoxyphenyl)glycidic acid methyl ester [Eq. (13)], a precursor in the preparation of the calcium antagonist drug diltiazem (91) ... 

Syntheses of relatively simple chiral drugs on an industrial scale are the domain of catalytic or enzymatic methods. In the case of the calcium antagonist diltiazem [113] Sharpless asymmetric dihydroxylation (AD-reaction) is employed which works particularly efficiently for cinnamic acid derivatives such as 48-1. In fact diol 48-2 is obtained with good optical enrichment and is then converted into the target compound via 6 routine steps. Alternatively diltiazem is prepared via classical optical resolution or via enzymatic kinetic resolution of suitable intermediates [113]. 

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. 

Ishii, K. Minato, K. Nishimura, N. Miyamoto, T Sato, T. Direct chromatographic resolution of four optical isomers of diltiazem hydrochloride on a Chiralcel OF column. J.Chromatogr., 1994, 686, 93— 100 [chiral column temp 10-40]... 

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. 

Diltiazem Lipase Resolution will be achieved by preferential hydrolysis of starting racemic p-methoxy-phenylglycidate [70]... 

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... 

For membrane solvent extraction, Schlosser et al. [114] provided a comprehensive review for organic acid separation and recovery. Large-scale utilization of membrane solvent extraction [107,115,116] modules in pharmaceutical/chemical plants is used. Lopez and Matson [115] demonstrated enzymatic resolution of diltiazem precursor using hydrophilic polyacrylonitrile hollow fibers and an aqueous-organic interface on the outside surface of these fibers. Klaassen and Jansen [116] and Porebski et al. [107] illustrated the use/ performances of modules of porous hydrophobic PP hollow fibers in chemical plants achieving aqueous-to-organic and organic-to-aqueous solvent extraction, respectively. 

The bank of 60 m commercial-scale membrane reactor modules in diltiazem production facility employing hydrophilic polyaCTylonitrile hollow fibers was demonstrated. This example describes enzymatic resolution of diltiazem precursor using hydrophilic polyacrylonitrile hollow fibers and an aqueous-organic interface on the outside surface of these fibers (Eigure 4.16) [1,3,116]. 

Yaku K, Aoe K, Nishimura N, Sato T, Morishita F (1997) Chiral resolution of four optical isomers of diltiazem hydrochloride on Chiralcel columns by packed-column supercritical fluid chromatography. J Chromatogr A 785 185-193... 

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