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

合成路线: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)

参考文献标题:Chiral arylpropionates and their use
文献作者:McCague,R.; Wang,S.; Taylor,S.J.C.(Celltech Group plc)
参考来源:WO 9413828


合成路线: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)

参考文献标题:Process for preparing optically active phenyloxirane cpds.
文献作者:Ozaki,Y.; Arakawa,H.; Harada,N.; Hashiyama,T.; Kuroda,T.; Seki,M.; Kusama,M.(Tanabe Seiyaku Co.,Ltd.)
参考来源:WO 9856762


合成路线:Addition of phenylmagnesium bromide to cyclohexene oxide (XXI) in the presence of CuCl gave trans-2-phenylcyclohexanol (XXII),which was further esterified with chloroacetyl chloride to afford 2-phenylcyclohexyl chloroacetate (XXIII).Enantioselective hydrolysis of the racemic ester (XXIII) by means of Pseudomonas fluorescens lipase provided pure (1R,2S)-2-phenylcyclohexanol (XXIV),which was again esterified with chloroacetyl chloride,yielding the chiral ester (XXVI).Darzen's condensation of chloro ester (XXVI) with anisaldehyde (X) led to the chiral glycidic ester (XXVII).Epoxide ring opening in (XXVII) with 2-aminothiophenol (VII) furnished amino ester (XXVIII).Intermediate thiazepinone (VIII) was then obtained by cyclization of (XXVIII) using p-toluenesulfonic acid in refluxing xylene.Alternatively,amino ester (XXVIII) was first hydrolyzed to amino acid (XXIX),which was subsequently cyclized with p-toluenesulfonic acid as above (11).The final cyclization of amino acid (XXIX) to the intermediate thiazepinone (VIII) has also been carried out in the presence of trichloroacetic acid

参考文献标题:Process for the preparation of a benzothiazepine
文献作者:Plaum,M.J.M.; Boesten,W.H.J.
参考来源:EP 0796853; JP 1998007667; US 5859241


合成路线:In a further process,the racemic trans glycidic ester (XII),prepared by Darzen's 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

合成路线:Alkylation of the lactam N of thiazepinone (I) with 2-(dimethylamino)ethyl chloride (II) in the presence of K2CO3 or under phase-transfer conditions gave thiazeinone (III).Subsequent esterification of (III) with acetic anhydride furnished the title compound.Alternatively,diltiazem has been prepared by acetylation of thiazeinone (I) with Ac2O to yield the lactam acetate ester (IV),which is then alkylated with chloride (II) under phase-transfer conditions

参考文献标题:Process for preparing diltiazem
文献作者:Bhushan,L.B.; Jayachandran,B.E.; Bhushan,L.V.; Thottappillil,R.(Council of Scientific and Industrial Research)
参考来源:US 5869697


合成路线:Alkylation of the lactam N of thiazepinone (I) with 2-(dimethylamino)ethyl chloride (II) in the presence of K2CO3 or under phase-transfer conditions gave thiazeinone (III).Subsequent esterification of (III) with acetic anhydride furnished the title compound.Alternatively,diltiazem has been prepared by acetylation of thiazeinone (I) with Ac2O to yield the lactam acetate ester (IV),which is then alkylated with chloride (II) under phase-transfer conditions

参考文献标题:A process for the preparation of diltiazem
文献作者:Piselli,F.L.; Boschi,P.; Navoni,C.
参考来源:EP 0594101


合成路线:Alkylation of the lactam N of thiazepinone (I) with 2-(dimethylamino)ethyl chloride (II) in the presence of K2CO3 or under phase-transfer conditions gave thiazeinone (III).Subsequent esterification of (III) with acetic anhydride furnished the title compound.Alternatively,diltiazem has been prepared by acetylation of thiazeinone (I) with Ac2O to yield the lactam acetate ester (IV),which is then alkylated with chloride (II) under phase-transfer conditions

参考文献标题:Method for the manufacture of benzothiazepine derivs.
文献作者:Murthy,K.; Weeratunga,G.; Burchat,A.(ACIC (Canada) Inc.)
参考来源:WO 9638429