Synthesis of 1, 5-Benzothiazepine Derivatives. I

Kugita, Hiroshi; Inoue, Hirozumi; Ikezaki, Muneyoshi; Takeo, Satoshi

doi:10.1248/cpb.18.2028

Cited by 44 publications

(8 citation statements)

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“…Our prior work has shown that reaction of the trans-3-(4-methoxyphenyl)glycidic ester (2a) with 2-nitrothiophenol (1) mainly gives the threo-nitro ester (3a-t), the cis-product resulting from front-side opening of the oxirane ring, after prolonged heating in MeCN. 2 However, this procedure suffers from¯aws such as low yield (`60%), insuf®cient stereoselectivity, and long reaction time, which have been obstacles in the synthesis of diltiazem. The reaction of 1 and 2a in the presence of a catalytic amount of NaHCO 3 , on the other hand, readily gave the undesired erythro-isomer (3a-e), the trans-opening product resulting from back-side S N 2-type attack of thiolate anion as shown in Figure 2.…”

Section: Introductionmentioning

confidence: 99%

Applications of Lewis acids for the efficient syntheses of diltiazem, cephems, and taxoids

Hashiyama

2000

Med. Res. Rev.

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An efficient method is described for preparation of diltiazem hydrochloride (Herbesser®), a marketed calcium antagonist widely used for the treatment of ischemic heart disease. In the reaction of 2‐nitrothiophenol (1) with trans‐3‐phenylglycidic esters (2) carrying various substituents on the benzene ring, both reactivity and stereoselectivity of the oxirane ring‐opening of the glycidates were markedly influenced by the electronic nature of the substituents. As a result of our investigation on the catalytic effect of various Lewis acids in the reaction of 2a with 1, tin compounds were found to be effective catalysts for the cis‐opening and readily produced the threo‐nitro ester (3a‐t), a key intermediate for the synthesis of diltiazem. Isolation of the crystalline complex from the reaction of 1 and SnCl4; and its efficient catalytic activity similar to that of SnCl4 suggests that the transition state involves co‐coordination of tin derivatives both with 1 and the epoxy oxygen of 2a to result in highly specific cis‐opening. We have also amplified this chemistry into other fields, leading to applications in the syntheses of cephem and taxoid templates. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 6, 485–501, 2000

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Section: Introductionmentioning

confidence: 99%

Applications of Lewis acids for the efficient syntheses of diltiazem, cephems, and taxoids

Hashiyama

2000

Med. Res. Rev.

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“…Search of Chiral Sources. The ketone 3 was prepared by oxidation 6,8 of the racemic alcohol (2 RS ,3 RS )- 1 , followed by ester hydrolysis. With chiral reducing agents prepared from NaBH 4 and various α-amino acids, 3 was asymmetrically reduced to the corresponding stereoisomer of 1 .…”

Section: Resultsmentioning

confidence: 99%

Asymmetric Reduction of a 1,5-Benzothiazepine Derivative with Sodium Borohydride−(S)-α-Amino Acids: An Efficient Synthesis of a Key Intermediate of Diltiazem

et al. 1996

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A key intermediate of diltiazem synthesis, (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [(2S,3S)-1], has been efficiently synthesized by an asymmetric reduction of the prochiral ketone, 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (3), with NaBH4 and chiral α-amino acids. As the chiral sources, β-branched-chain amino acids, such as (S)-valine, (S)-isoleucine, and (S)-tert-leucine, were found to be effective. In particular, using (S)-tert-leucine as a ligand resulted in the formation of (2S,3S)-1 with excellent enantioselectivity. (95% ee for cis-isomers). The addition of AcOH to the reaction permitted further improvement of both conversion and stereoselectivity. As a result, optically pure (2S,3S)-1 could be isolated in 86% yield. This asymmetric reduction proceeded via dynamic kinetic resolution and made it possible to control the two adjacent asymmetric carbons through keto−enol tautomerism.

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“…58 (m, 1 H, C-8 H), 1.12-1.27 (m, 1 H, C-8 ), 1.01-1.10 (m, 1 H, C-15 ), 0.72-0.87 (m, 1 H, C-18 ), 0.45-0.55 (m, 2 H, C-19 H, C-20 ), 0.03-0.13 (m, 2 H, C-19 H', C-20 H'). 17-(Cyclopropylmethyl)-3-(triphenylmethoxy)-4,5aepoxy-6/?-[(3-cyanobenzyl)oxy]-14-hydroxymorphinan (15). Compound 15 was prepared by the phase transfer alkylation method described for preparation of 16.…”

Section: General Methodsmentioning

confidence: 99%

“…Formation of the analogous orthoand meta-alkylated products (14 and 15) required some modification of the PTC conditions (concentration of KOH, benzyl halide concentration and temperature, see Experimental Section). Catalytic reduction of the 3-0-trityl-6/3-0-cyanobenzyl ethers [14][15][16] gave (aminomethyl)benzyl ethers 17-19. Loss of the trityl group occurred in the aqueous acetic acid used as the solvent for the catalytic reduction.…”

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confidence: 99%

Isothiocyanate-Substituted Benzyl Ether Opioid Receptor Ligands Derived from 6.beta.-Naltrexol

Davis

Nelson

1995

J. Med. Chem.

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A series of regioisomeric substituted 6-O-benzyl ethers of 6 beta-naltrexol (12) in which isothiocyanate groups were attached directly to or one carbon removed from the aromatic ring of the benzyl group were prepared. These agents were prepared to obtain electrophilic opioid ligands potentially useful in the characterization of opioid receptors and drug-receptor interactions. Preparation of these ligands was accomplished from 3-O-trityl-6 beta-naltrexol (13) via phase transfer-catalyzed alkylation of the regioisomeric o-, m-, and p-nitrobenzyl halides and the o-, m-, and p-cyanobenzyl halides. The intermediates were deprotected and reduced, and formation of the isothiocyanates from the corresponding amines completed the synthesis. The ligands (6-11) were tested in radioligand displacement assays in guinea pig brain homogenate for opioid receptor binding affinity and irreversibility. All six of the isothiocyanates demonstrated significant affinity in the displacement assays for all three opioid receptors. They also appeared to be irreversibly bound at each of the receptor types. Compound 6, the o-isothiocyanatobenzyl ether analog, had the highest affinity, and it demonstrated significant irreversibility at very low concentration. It appears to be suitable for further investigation.

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Synthesis of 1, 5-Benzothiazepine Derivatives. I

Cited by 44 publications

References 0 publications

Applications of Lewis acids for the efficient syntheses of diltiazem, cephems, and taxoids

Applications of Lewis acids for the efficient syntheses of diltiazem, cephems, and taxoids

Asymmetric Reduction of a 1,5-Benzothiazepine Derivative with Sodium Borohydride−(S)-α-Amino Acids: An Efficient Synthesis of a Key Intermediate of Diltiazem

Isothiocyanate-Substituted Benzyl Ether Opioid Receptor Ligands Derived from 6.beta.-Naltrexol

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