Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution

Abstract

An efficient synthesis of diltiazem has been developed using dynamic kinetic resolution (DKR) as a key step. The methyl (2S,3S)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propionate was synthesized from a racemic mixture of a-chloro-b-keto ester, with high anti diastereoselectivity (92%) and enantioselectivity (95%), based on an asymmetric hydrogenation reaction with a chiral ruthenium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylallyl) 2 with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment of this a-chloro-b-hydroxy ester with a base, the corresponding trans methyl glycidate, a key intermediate of diltiazem, was easily obtained.Diltiazem (1), a typical calcium channel blocker, is commonly used for the treatment of angina pectoris and hypertension. 3 Only the (+)-(2S,3S)-isomer among the four possible stereoisomers presents this potent coronary vasodilating activity, therefore diltiazem has been developed and marketed as a single stereoisomer. For its synthesis, many pathways had been investigated and the trans methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2 was recognized as a practical and efficient intermediate ( Figure 1). A large number of formal synthesis of (-)-2 have been reported using various strategies including asymmetric epoxidations, 4 aldol 5 or Darzens 6 reactions, asymmetric reductions, 7 preferential crystallizations 8 or enzymatic approaches. 9 At the industrial scale, (-)-2 has been prepared by enzymatic resolution of the racemic glycidate (±)-2 based on a lipase-catalyzed enantioselective hydrolysis; 9c however the maximum yield cannot exceed 50%. In spite of all these studies, there is still a need for developing an efficient process for the synthesis of enantiopure (-)-2 in terms of yield, stereoselectivity and amount of chiral material at stake in the key step.In our continuous work on ruthenium-catalyzed asymmetric hydrogenation, 10 and its applications to the synthesis of biologically and industrially relevant molecules, 11 we report in this paper an asymmetric synthesis of diltiazem (1) based on the dynamic kinetic resolution of a racemic a-chloro-b-keto ester. The asymmetric hydrogenation of a-substituted b-keto ester bearing a configurationally labile stereogenic center with chiral Ru(II) catalysts is known to give preferentially one of the four possible diastereoisomers via dynamic kinetic resolution (DKR), 12 under optimized conditions. The selectivity of this DKR has already been studied by Noyori and our group and depends on the nature of the group borne at the a-position and on the reaction conditions. Whereas the hydrogenation of a-acetamido-b-keto esters 13 gave the syn adducts, cyclic a-alkyl-b-keto esters 14,12a,b or g-amino-a-methyl-bketo esters derived from (S)-proline 15 were reduced to the corresponding anti a-substituted b-hydroxy esters. Some preliminary studies on the asymmetric hydrogenation of a-chloro-b-keto esters 16a indicated that the anti diastereoisomer could also be obtained. 16b Therefore, the retrosynthetic plan (Scheme 1) we chose for diltiaz...

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

“…To date, more synthetic routes to prepare (+)-diltiazem 3 from a chiral epoxide intermediate have been reported. The enantiomerically pure epoxide has been obtained by the introduction of a chiral auxiliary in the reaction [295,296] , utilization of Yang's catalyst [297] , addition of metal complexes [298] or by direct acquisition. [299] A useful synthetic methodology employed to induce chirality in the product is the utilization of lipase [300,301] or baker's yeast catalysed reactions.…”

Palladium-catalyzed asymmetric allenylic alkylation: construction of multiple chiral thiochromanone derivatives

“…Organic sulfur compounds play important roles in pharmaceuticals, natural products and other fields, in which molecules containing chiral cyclic sulfide skeletons generally have special biological activity. 1 For example, diltiazem ( A ), 2 a a calcium channel blocking agent, is used for treating supraventricular tachycardia, a rhythm disturbance of the heart. Additionally, the rivastigmine analogue ( B ) 2 b is synthesized as an acetylcholine-esterase (AChE) inhibitor for the treatment of Alzheimer's disease, and 7-thia-DCK ( C ) 2 c is an anti-AIDS agent (Scheme 1).…”

Sustainable asymmetric synthesis of diltiazem precursor enabled by recombinant Escherichia coli whole cells co‐expressing an engineered ketoreductase and glucose dehydrogenase

“…Methyl (2R,3S)-3-(4-methoxyphenyl) glycidate, also known as (2R,3S)-MPGM (1) (Figure 1), is a crucial synthetic intermediate of diltiazem hydrochloride (Figure 1), which is a well-known calcium channel blocker and clinically employed for the treatment of hypertension and angina worldwide. [1][2][3] Among the various methods developed for the synthesis of 1, such as Darzens reactions [4] and…”

“…Methyl (2 R ,3 S )‐3‐(4‐methoxyphenyl) glycidate, also known as (2 R ,3 S )‐MPGM ( 1 ) (Figure 1), is a crucial synthetic intermediate of diltiazem hydrochloride (Figure 1), which is a well‐known calcium channel blocker and clinically employed for the treatment of hypertension and angina worldwide. [ 1–3 ] Among the various methods developed for the synthesis of 1 , such as Darzens reactions [ 4 ] and asymmetric epoxidation, [ 5 ] base‐mediated intramolecular ring closure of the preformed chlorohydrin (3 S )‐methyl 2‐chloro‐3‐hydroxy‐3‐(4‐methoxyphenyl)propanoate ((3 S )‐ 2 , Figure 1) is undoubtedly one of the most efficient and stereoselective approaches. [ 6,7 ] Notably, both the (2 S ,3 S )‐ and (2 R ,3 S )‐diastereomers of (3 S )‐ 2 can be converted to (2 R ,3 S )‐MPGM under the reaction conditions employed.…”