盐酸地尔硫卓合成图解

盐酸地尔硫卓合成图解 Chemical Name ：

cis-(+)-3-Acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaz epin-4(5H)-one hydrochloride

Generic

Name ：

盐酸地尔硫卓;Dilthiazem hydrochloride Other Names ：

Diltiazem hydrochloride;CRD-401;MK-793(maleate);SLV-324;Milptin;Teczem(Comb. with enalapril);Tiazac(slow-release);Herbesser;Adizem;Dilzem;Cardizem;Slozem;Cardizem XL;Masdil;Uni-Masdil;Anoheal;Lacerol;Cardizem LA;Tildiem CAS ： 33286-22-5

Related

CAS ： 42399-41-7 (free base), 144604-00-2 (monomaleate)

Formula ： C 22H 27ClN 2O 4S

Mole

Weight ： 450.98849

structure ：

Company ：

Biovail (Originator), Tanabe Seiyaku (Originator), Elan (Not Determined), Sanofi-Synthélabo (Not Determined), Solvay (Marketer), Aventis Pharma (Licensee), Esteve (Licensee), Forest (Licensee), Lacer (Licensee), SLA Pharma (Licensee), DOV Pharmaceutical (

Usage ： Angina pectoris, Treatment of, Anorectal Disorders, Treatment of, Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, GASTROINTESTINAL DRUGS, Heart Failure Therapy,

Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and

Atherosclerosis, Calcium Channel Blockers

Route 1

Electrophilic bromination of ethyl p-methoxycinnamate (I) by means of N-bromosuccinimide in moist acetone gave rise to the racemic erythro bromohydrin (II), which was esterified with butyric anhydride to produce the racemic bromoester (III). Kinetic resolution of (III) employing Candida cylindracea lipase caused the enantioselective hydrolysis of the (S,S)-enantiomer, yielding the chiral bromohydrin (V). Cyclization of (V) in the presence of NaOMe furnished epoxide (VI). The target thiazepinone (VIII) was then obtained by condensation between the glycidic ester (VI) and 2-aminobenzenethiol (VII)

Intermediates: Seri al No.

1S,5R,13R,16S,17R)-4-cyano-16-ethyl-10-methoxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,1

8)]octadeca-7(18),8,10-trien-14-one

(A)

[(2R,3S,5R)-5-(6-hydroxy-9H-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (VII

)

Reference 1:

McCague, R.; Wang, S.; Taylor, S.J.C. (Celltech Group plc); Chiral arylpropionates and their use. WO 9413828 .

Route 2

A different method for the preparation of glycidic ester (VI) consists in the asymmetric epoxidation of ethyl 4-methoxycinnamate (I) with oxone(R) in the presence of chiral macrocyclic ketones, such as the binaphthyl ketone (IX)

Intermediates: Serial No.

Reference 1:

Seki, M.; Furutani, T.; Imashiro, R.; Kuroda, T.; Yamanaka, T.; Harada, N.; Arawaka, H.; Kusama, M.; Hashiyama, T.; A novel synthesis of a key intermediate for diltiazem. Tetrahedron Lett 2001, 42, 46, 8201. Reference 2:

Ozaki, Y.; Arakawa, H.; Harada, N.; Hashiyama, T.; Kuroda, T.; Seki, M.; Kusama, M. (Tanabe Seiyaku Co., Ltd.); Process for preparing optically active phenyloxirane cpds.. WO 9856762 .

Route 3

In a further process, the racemic trans glycidic ester (XII), prepared by Darzens condensation between anisaldehyde (X) and methyl chloroacetate (XI), was resolved by enantioselective enzymatic hydrolysis, using several different enzymes and reaction conditions to produce the undesired (2S,3R) acid (XIII), while leaving intact the required (2R,3S)-glycidic ester (XIV) (4-7). Opening of the chiral epoxide (XIV) with

2-aminobenzenethiol (VII) proceeded with retention of the configuration, producing methyl

(2S,3S)-2-hydroxy-3-(2-aminophenylsulfanyl)-3-(4-methoxyphenyl)propionate (XV) (8). Alternatively, the (S,S)-amino ester (XV) was obtained by resolution with tartaric acid of the racemic three-adduct resulting from epoxide (XII) and 2-aminobenzenethiol (VII) (9). Cyclization of amino ester (XV) in refluxing xylene in the presence of p-toluenesulfonic acid afforded the target lactam (VIII) (9). The cyclization of (XV) to lactam (VIII) was also accomplished by means of trichloroacetic acid or under basic conditions