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【结 构 式】

【药物名称】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

【化学名称】cis-(+)-3-Acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride

【CA登记号】33286-22-5, 42399-41-7 (free base), 144604-00-2 (monomaleate)

【 分 子 式 】C22H27ClN2O4S

【 分 子 量 】450.98849

【开发单位】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 (

【药理作用】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
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17

合成路线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)

参考文献 中间体
【1】 McCague, R.; Wang, S.; Taylor, S.J.C. (Celltech Group plc); Chiral arylpropionates and their use. WO 9413828 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 25047 butyric anhydride 106-31-0 C8H14O3 详情 详情
(I) 62431 ethyl (E)-3-(4-methoxyphenyl)-2-propenoate C12H14O3 详情 详情
(II) 62432 ethyl (2S,3S)-2-bromo-3-hydroxy-3-(4-methoxyphenyl)propanoate C12H15BrO4 详情 详情
(III) 62433 (1S,2S)-2-bromo-3-ethoxy-1-(4-methoxyphenyl)-3-oxopropyl butyrate C16H21BrO5 详情 详情
(IV) 62434 (1R,2R)-2-bromo-3-ethoxy-1-(4-methoxyphenyl)-3-oxopropyl butyrate C16H21BrO5 详情 详情
(V) 62432 ethyl (2S,3S)-2-bromo-3-hydroxy-3-(4-methoxyphenyl)propanoate C12H15BrO4 详情 详情
(VI) 62435 ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C12H14O4 详情 详情
(VII) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(VIII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情

合成路线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)

参考文献 中间体
【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.
【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 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62431 ethyl (E)-3-(4-methoxyphenyl)-2-propenoate C12H14O3 详情 详情
(VI) 62435 ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C12H14O4 详情 详情
(IX) 62437 9H-dinaphtho[2,1-g:1,2-i][1,5]dioxacycloundecine-7,10,13(11H)-trione C25H16O5 详情 详情

合成路线3

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

参考文献 中间体
【1】 Bhushan, L.B.; Jayachandran, B.E.; Bhushan, L.V.; Thottappillil, R. (Council of Scientific and Industrial Research); Process for preparing diltiazem. US 5869697 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(VIII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(X) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(XI) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(XII) 11905 methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C11H12O4 详情 详情
(XIII) 62438 (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylic acid C10H10O4 详情 详情
(XIV) 62435 ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C12H14O4 详情 详情
(XV) 62439 methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate C17H19NO4S 详情 详情

合成路线4

A new enantioselective method for the preparation of glycidic ester (XIV) has been disclosed. Methyl trichloroacetate (XVI) was converted to the dichloroketene silyl acetal (XVII) by treatment with zinc powder and chlorotrimethylsilane. Asymmetric aldol condensation of (XVII) with anisaldehyde (X) in the presence of the chiral oxazaborolidine catalyst (XVIII) at -78 C produced methyl (S)-2,2-dichloro-3-hydroxy-3-(4-methoxyphenyl)propionate (XIX). Reductive mono-dechlorination of (XIX) furnished chlorohydrin (XX), which was then cyclized to glycidic ester (XIV) in the presence of NaOMe

参考文献 中间体
【1】 Imashiro, R.; Kuroda, T.; Asymmetric synthesis of methyl (2R,3S)-3-(4-methoxyphenyl) glycidate, a key intermediate of diltiazem, via Mukaiyama aldol reaction. Tetrahedron Lett 2001, 42, 7, 1313.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(XIV) 62435 ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C12H14O4 详情 详情
(XVI) 62440 methyl 2,2,2-trichloroacetate 598-99-2 C3H3Cl3O2 详情 详情
(XVII) 62441 　 C4H6Cl2O2 详情 详情
(XVIII) 62442 　 C6H12BNO2 详情 详情
(XIX) 62443 methyl (3S)-2,2-dichloro-3-hydroxy-3-(4-methoxyphenyl)propanoate C11H12Cl2O4 详情 详情
(XX) 62444 methyl (3S)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propanoate C11H13ClO4 详情 详情

合成路线5

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 中间体
【1】 Plaum, M.J.M.; Boesten, W.H.J.; Process for the preparation of a benzothiazepine. EP 0796853; JP 1998007667; US 5859241 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(+/-)-(XXII) 51208 (1R,2S)-2-phenylcyclohexanol C12H16O 详情 详情
(+/-)-(XXIII) 62445 (1S,2R)-2-phenylcyclohexyl 2-chloroacetate C14H17ClO2 详情 详情
(VII) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(VIII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(X) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(XXI) 17986 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide 286-20-4 C6H10O 详情 详情
(XXIV) 10492 (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol 2362-61-0 C12H16O 详情 详情
(XXV) 62445 (1S,2R)-2-phenylcyclohexyl 2-chloroacetate C14H17ClO2 详情 详情
(XXVI) 62445 (1S,2R)-2-phenylcyclohexyl 2-chloroacetate C14H17ClO2 详情 详情
(XXVII) 62446 (1R,2S)-2-phenylcyclohexyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C22H24O4 详情 详情
(XXVIII) 62447 (1R,2S)-2-phenylcyclohexyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate C28H31NO4S 详情 详情
(XXIX) 62448 (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid C16H17NO4S 详情 详情

合成路线6

A different strategy to reach the amino ester precursor (XXIX) was developed starting from the chiral diol (XXX), readily accessible by asymmetric dihydroxylation of cinnamate (I). Reaction of diol (XXX) with SOCl2 produced the cyclic sulfite (XXXI) (12,14). Optionally, diol (XXX) was condensed with phosgene to produce the cyclic carbonate (XXXII) (12). Opening of either sulfite (XXXI) or carbonate (XXXII) with 2-aminothiophenol (VIII) proceeded with retention of the configuration, leading to the desired intermediate aminoacid (XXIX)

参考文献 中间体
【1】 Lohray, B.B.; Jayachandran, B.; Bhushan, V.; Nandanan, E.; Ravindranathan, T.; Anchimeric assisted unprecedented SN(i)-type cleavage of cyclic sulfite: Application in the synthesis of the calcium channel blocker diltiazem. J Org Chem 1995, 60, 18, 5983.
【2】 Hulshof, L.A.; Kuilman, T.; Process for preparing 1,5-benzothiazepin derivs.. EP 0450705 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62431 ethyl (E)-3-(4-methoxyphenyl)-2-propenoate C12H14O3 详情 详情
(VIII) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(XXIX) 62448 (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid C16H17NO4S 详情 详情
(XXX) 62449 ethyl (2R,3S)-2,3-dihydroxy-3-(4-methoxyphenyl)propanoate C12H16O5 详情 详情
(XXXI) 62450 ethyl (4R,5S)-5-(4-methoxyphenyl)-2-oxo-1,3,2lambda~4~-dioxathiolane-4-carboxylate C12H14O6S 详情 详情
(XXXII) 62451 ethyl (4R,5S)-5-(4-methoxyphenyl)-2-oxo-1,3-dioxolane-4-carboxylate C13H14O6 详情 详情

合成路线7

The racemic thiazepinone (XXXIII) has been converted to the pure enantiomer (VIII) through a different strategy. Oxidation of hydroxy lactam (XXXIII) by means of DMSO and Ac2O produced the enol ester (XXXV). Basic hydrolysis of (XXXI) gave rise to the keto lactam (XXXV). This was then subjected to asymmetric reduction utilizing a reducing reagent generated in situ from NaBH4 and (S)-tert-leucine to afford the intermediate thiazepinone (VIII)

参考文献 中间体
【1】 Yamada, S.; Mori, Y.; Morimatsu, K.; Ishizu, Y.; Ozaki, Y.; Yoshioka, R.; Nakatani, T.; Seko, H.; Asymmetric reduction of a 1,5-benzothiazepine derivative with sodium borohydride-(S)-alpha-amino acids: An efficient synthesis of a key intermediate of diltiazem. J Org Chem 1996, 61, 24, 8586.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
28445 (2S)-2-amino-3,3-dimethylbutyric acid C6H13NO2 详情 详情
(VIII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(XXXIII) 63413 (6-bromo-3-pyridinyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone C13H15BrN2O3 详情 详情
(XXXIV) 62452 2-(4-methoxyphenyl)-4-oxo-4,5-dihydro-1,5-benzothiazepin-3-yl acetate C18H15NO4S 详情 详情
(XXXV) 62453 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione C16H13NO3S 详情 详情

合成路线8

The precursor cis-cinnamate (XXXIX) can be obtained by several synthetic routes. Bromination of ethyl trans-4-methoxycinnamate (I) afforded the dibromo ester (XXXVI), which underwent dehydrohalogenation and hydrolysis to the arylpropiolic acid (XXXVII) upon treatment with ethanolic KOH. Acid (XXXVII) was converted to the corresponding isopropyl ester (XXXVIII) by DCC-mediated coupling with isopropanol. Semihydrogenation of (XXXVIII) in the presence of Lindlar catalyst led to the required cis cinnamate (XXXIX). Alternatively, anisaldehyde (X) was converted to the gem-dibromostyrene (XL) by condensation with CBr4 in the presence of PPh3. Reaction of (XL) with BuLi, followed by addition of isopropyl chloroformate to the resultant lithium acetylide, furnished the arylpropiolate (XXXVIII). In another method to obtain the cis-cinnamate (XXXIX), trans-4-methoxycinnamic acid (XLI) was converted to the isopropyl ester (XLII), which was then photochemically isomerized to the desired cis-cinnamate (XXXIX)

参考文献 中间体
【1】 Jacobsen, E.N.; Deng, L.; Furukawa, Y.; Martinez, L.E.; Enantioselective catalytic epoxidation of cinnamate esters. Tetrahedron 1994, 50, 15, 4323.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62431 ethyl (E)-3-(4-methoxyphenyl)-2-propenoate C12H14O3 详情 详情
(X) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(XXXVI) 62454 ethyl 2,3-dibromo-3-(4-methoxyphenyl)propanoate C12H14Br2O3 详情 详情
(XXXVII) 62455 3-(4-methoxyphenyl)-2-propynoic acid C10H8O3 详情 详情
(XXXVIII) 62457 isopropyl 3-(4-methoxyphenyl)-2-propynoate C13H14O3 详情 详情
(XXXIX) 62458 isopropyl (Z)-3-(4-methoxyphenyl)-2-propenoate C13H16O3 详情 详情
(XL) 62456 1-(2,2-dibromovinyl)-4-methoxybenzene; 4-(2,2-dibromovinyl)phenyl methyl ether C9H8Br2O 详情 详情
(XLI) 42108 (E)-3-(4-methoxyphenyl)-2-propenoic acid 830-09-1 C10H10O3 详情 详情
(XLII) 63416 isopropyl (E)-3-(4-methoxyphenyl)-2-propenoate C13H16O3 详情 详情

合成路线9

The key cis glycidate ester (XLIII) was prepared by (salen)Mn(III)-catalyzed asymmetric epoxidation of the cis cinnamate (XXXIX). Epoxide opening in (XLIII) with 2-nitrothiophenol (XLIV), with inversion of the configuration, led to the nitro ester adduct (XLV). The nitro group of (XLV) was then reduced to the aniline derivative (XLVI) by means of FeSO4. Subsequent isopropyl ester group saponification in (XLVI) furnished amino acid (XXIX). This was then cyclized to the target thiazepinone (VIII) in refluxing xylene

参考文献 中间体
【1】 Jacobsen, E.N.; Deng, L.; Furukawa, Y.; Martinez, L.E.; Enantioselective catalytic epoxidation of cinnamate esters. Tetrahedron 1994, 50, 15, 4323.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
62502 4-Picoline N-oxide; 4-Methyl-1-pyridiniumolate 1003-67-4 C6H7NO 详情 详情
(VIII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(XXIX) 62448 (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid C16H17NO4S 详情 详情
(XXXIX) 62458 isopropyl (Z)-3-(4-methoxyphenyl)-2-propenoate C13H16O3 详情 详情
(XLIII) 62459 isopropyl (2R,3R)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C13H16O4 详情 详情
(XLIV) 62460 2-nitrobenzenethiol; 2-nitrophenylhydrosulfide C6H5NO2S 详情 详情
(XLV) 62461 isopropyl (2S,3S)-2-hydroxy-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C19H21NO6S 详情 详情
(XLVI) 62462 isopropyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate C19H23NO4S 详情 详情

合成路线10

In a variation of the preceding methods, the chiral glycidic amide (XLVII) was used as the synthetic precursor. Amide (XLVII) was either prepared by treatment of the chiral glycidic ester (VI) with ammonia, or by enzymatic resolution of (XII), followed by amidation. Iron-catalyzed addition of 2-aminothiophenol (VII) to the glycidamide (XLVII) in refluxing chlorobenzene yielded the desired threo adduct (XLVIII) as the major isomer. Cyclization of amino amide (XLVIII) under acidic conditions furnished thiazepinone (VIII)

参考文献 中间体
【1】 Yamada, S.; Tsujioka, I.; Shibatini, T.; Yoshioka, R.; Efficient alterative synthetic route to diltiazem via (2R,3S)-3-(4-methoxyphenyl)glycidamide. Chem Pharm Bull 1999, 47, 2, 146.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 62435 ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C12H14O4 详情 详情
(VII) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(VIII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(XII) 11905 methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C11H12O4 详情 详情
(XLVII) 62463 (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxamide C10H11NO3 详情 详情
(XLVIII) 62464 (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanamide C16H18N2O3S 详情 详情

合成路线11

Aldol condensation of anisaldehyde (X) with the lithium enolate of the N-acyl oxazolidinone (XLIX) gave adduct (L). Dehydration of alcohol (L) was accomplished by formation of the corresponding mesylate (LI), which underwent elimination in the presence of DBU, to produce a 4:1 mixture of Z and E olefins. After chromatographic isolation of the major Z isomer (LII), diastereoselective Michael addition using a 1:2 mixture of 2-aminothiophenol (VII) and the corresponding lithium thiophenoxide furnished (LIII) as the major diastereoisomer. Intramolecular cyclization of the amino imide (LIII) to the benzothiazepinone (LIV) was accomplished in the presence of trimethylaluminium in refluxing CH2Cl2. The methoxymethyl group of (LIV) was then removed by treatment with TiCl4, leading to the key precursor the thiazepinone (VIII)

参考文献 中间体
【1】 Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T.; Asymmetric construction of two contiguous stereocenters by diastereoface differentiating addition reaction of thiols to chiral imides: Formal synthesis of (+)-diltiazem. Tetrahedron 1997, 53, 7, 2421.
【2】 Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T.; Asymmetric induction at two contiguous stereogenic centers by diastereoface differentiating nucleophilic addition reaction. Tetrahedron Lett 1991, 32, 29, 3519.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(VIII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(X) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(XLIX) 62465 (4S)-4-isopropyl-3-[2-(methoxymethoxy)acetyl]-1,3-oxazolidin-2-one C10H17NO5 详情 详情
(L) 62466 (4S)-3-[3-hydroxy-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one C18H25NO7 详情 详情
(LI) 62467 3-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-(methoxymethoxy)-1-(4-methoxyphenyl)-3-oxopropyl methanesulfonate C19H27NO9S 详情 详情
(LII) 62468 (4S)-4-isopropyl-3-[(Z)-2-(methoxymethoxy)-3-(4-methoxyphenyl)-2-propenoyl]-1,3-oxazolidin-2-one C18H23NO6 详情 详情
(LIII) 62469 (4S)-3-[(2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one C24H30N2O6S 详情 详情
(LIV) 62470 (2S,3S)-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C18H19NO4S 详情 详情

合成路线12

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 中间体
【1】 Coffen, D.L.; Madan, P.B.; Schwartz, A. (F. Hoffmann-La Roche AG); Process for the preparation of optically pure aminophenylthio- and aminonaphthalenylthio-propanoic acids. EP 0343474 .
【2】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 .
【3】 Murthy, K.; Weeratunga, G.; Burchat, A. (ACIC (Canada) Inc.); Method for the manufacture of benzothiazepine derivs.. WO 9638429 .
【4】 Piselli, F.L.; Boschi, P.; Navoni, C.; A process for the preparation of diltiazem. EP 0594101 .
【5】 Bhushan, L.B.; Jayachandran, B.E.; Bhushan, L.V.; Thottappillil, R. (Council of Scientific and Industrial Research); Process for preparing diltiazem. US 5869697 .
【6】 Hytonen, M. (Orion Corporation); Process for the manufacture of diltiazem. EP 0728751; JP 1996253464; US 5644054 .
【7】 Hulshof, L.A.; Kuilman, T.; Process for preparing 1,5-benzothiazepin derivs.. EP 0450705 .
【8】 Manghisi, E.; Cascio, G. (Lusofarmaco); Process for the optical resolution of the dl-alpha-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid. US 4533748 .
【9】 Simonovitch, H.; Hoffmann, T.; Sassoon, S. (Abic, Ltd.); A process for the preparation of benzothiazepin derivs.. EP 0158303 .
【10】 Hytonen, M. (Orion Corporation); Method for the preparation of pharmaceutically active benzothiazepine derivs.. EP 0702009 .
【11】 Manghisi, E.; Perego, B.; A process for the preparation of diltiazem. WO 9210485 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(III) 62488 (2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H24N2O3S 详情 详情
(IV) 62452 2-(4-methoxyphenyl)-4-oxo-4,5-dihydro-1,5-benzothiazepin-3-yl acetate C18H15NO4S 详情 详情

合成路线13

Similarly, thiazepinone (I) was transesterified with isopropenyl acetate (V) to afford acetate ester (IV). Subsequent alkylation of the lactam N of (IV) with 2-(dimethylamino)ethyl mesylate (VI) in the presence of K2CO3 furnished diltiazem. Similarly, thiazepinone (I) was transesterified with isopropenyl acetate (V) to afford acetate ester (IV). Subsequent alkylation of the lactam N of (IV) with 2-(dimethylamino)ethyl mesylate (VI) in the presence of K2CO3 furnished diltiazem.

参考文献 中间体
【1】 Harsanyi, K.; Gizur, T.; Demeter, A.; Aracs, Z.; Felmeri, J.; Berki, K.; Trischeler, F.; Vincze, Z. (Gedeon Richter Ltd.); Process for the preparation of benzothiazepin-4(5H)-one derivs.. ES 2001146; JP 1987108872 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(III) 62488 (2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H24N2O3S 详情 详情
(IV) 62490 (2S,3S)-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate C18H17NO4S 详情 详情
(V) 21178 isopropenyl acetate 108-22-5 C5H8O2 详情 详情
(VI) 62491 ethyl 3-chloro-3-(3-pyridinyl)propyl(methyl)carbamate C12H17ClN2O2 详情 详情

合成路线14

Several related procedures utilize racemic intermediates that are resolved in more advanced synthetic steps. The racemic trans-glycidic ester (IX) was prepared by Darzen's condensation between anisaldehyde (VII) and methyl chloroacetate (VIII). Opening of the epoxide group of (IX) with 2-aminothiophenol (X) in hot chlorobenzene in the presence of FeCl3 gave rise to the racemic threo adduct (XI) which, without isolation, was cyclized to the cis-lactam (XII) by addition of methanesulfonic acid and then heating to reflux. Alkylation of the lactam N of (XII) with 2-(dimethylamino)ethyl chloride (II) led to the racemic precursor (XIII). Resolution of (XIII) to provide the (S,S)-isomer (VII) was then accomplished by preferential crystallization of supersaturated solutions of several sulfonate salts of (XIII) upon seeding with the desired enantiomer. Racemic diltiazem (XIV), obtained by acetylation of (XIII), has been resolved via formation of the corresponding diastereoisomeric salts with (S)-naproxen

参考文献 中间体
【1】 Gizur, T.; Harsanyi, K.; Fogassy, E.; Studies of the resolution of racemates in the synthesis of diltiazem. J Prakt Chem Chem-Ztg 1994, 336, 7, 628.
【2】 Yamada, S.; Yoshioka, R.; Shibatani, T.; Optical resolution of a 1,5-benzothiazepine derivative,a synthetic intermediate of diltiazem, by preferential crystallization and diastereomeric salt formation. Chem Pharm Bull 1997, 45, 12, 1922.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(VII) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(VII) 62488 (2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H24N2O3S 详情 详情
(VIII) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(IX) 11905 methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C11H12O4 详情 详情
(X) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(XI) 62439 methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate C17H19NO4S 详情 详情
(XII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(XIII) 62487 5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H24N2O3S 详情 详情
(XIV) 62489 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate C22H26N2O4S 详情 详情

合成路线15

. 4-Hydroxycinnamic acid (XV) was acetylated with Ac2O in pyridine, and the resultant 4-acetoxycinnamic acid (XVI) was converted to the cinnamyl alcohol (XVIII) via conversion to the mixed anhydride (XVII) and subsequent reduction with NaBH4. Sharpless asymmetric epoxidation of (XVIII) furnished the chiral epoxide alcohol (XIX). After oxidation of alcohol (XIX) to the glycidic acid (XX) by means of RuO2/NaIO4, treatment with dimethyl sulfate and Et3N gave rise to the corresponding methyl ester (XXI). Epoxide opening in (XXI) with HCl and pyridine hydrochloride produced chlorohydrin (XXII) as a mixture of the desired (2S,3R)-isomer and minor amounts of the corresponding 3-chloro epimer. Condensation of (XXII) with 2-nitrothiophenol (XXIII) provided, after recrystallization from EtOH, the pure (S,S)-thioether adduct (XXIV). The hydroxyl group of (XXIV) was then protected as the methoxymethyl ether (XXV) by means of methylal in the presence of P2O5

参考文献 中间体
【1】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 37809 (E)-3-(4-Hydroxyphenyl)-2-propenoic acid; 4-Hydroxy cinnamic acid 501-98-4 C9H8O3 详情 详情
(XVI) 62479 (E)-3-[4-(acetyloxy)phenyl]-2-propenoic acid C11H10O4 详情 详情
(XVII) 62480 　 C14H14O6 详情 详情
(XVIII) 62481 4-[(E)-3-hydroxy-1-propenyl]phenyl acetate C11H12O3 详情 详情
(XIX) 62482 4-[(2S,3S)-3-(hydroxymethyl)oxiranyl]phenyl acetate C11H12O4 详情 详情
(XX) 62483 (2R,3S)-3-[4-(acetyloxy)phenyl]-2-oxiranecarboxylic acid C11H10O5 详情 详情
(XXI) 62484 methyl (2R,3S)-3-[4-(acetyloxy)phenyl]-2-oxiranecarboxylate C12H12O5 详情 详情
(XXII) 62485 methyl (2S)-3-[4-(acetyloxy)phenyl]-3-chloro-2-hydroxypropanoate C12H13ClO5 详情 详情
(XXIII) 62460 2-nitrobenzenethiol; 2-nitrophenylhydrosulfide C6H5NO2S 详情 详情
(XXIV) 62486 methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-hydroxy-3-[(2-nitrophenyl)sulfanyl]propanoate C18H17NO7S 详情 详情
(XXV) 62473 methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate C20H21NO8S 详情 详情

合成路线16

Selective hydrolysis of the acetate ester of (XXV) using benzylamine in THF led to phenol (XXVI), which was further methylated by means of diazomethane, yielding methyl ether (XXVII). Reduction of the nitro group (XXVII) to the corresponding aniline (XXVIII) was then performed employing ferrous sulfate and ammonium hydroxide. Subsequent saponification of the methyl ester group of (XXVIII) gave amino acid (XXIX). Cyclization of (XXIX) with ethyl chloroformate and triethylamine furnished lactam (XXX). The lactam N of (XXX) was then alkylated by 2-(dimethylamino)ethyl chloride (II) to produce (XXXI). Finally, deprotection of the methoxymethyl group of (XXXI) and concomitant O-acetylation was accomplished by treatment with acetyl chloride and TiCl4

参考文献 中间体
【1】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(XXV) 62473 methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate C20H21NO8S 详情 详情
(XXVI) 62474 methyl (2S,3S)-3-(4-hydroxyphenyl)-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate C18H19NO7S 详情 详情
(XXVII) 62475 methyl (2S,3S)-2-(methoxymethoxy)-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C19H21NO7S 详情 详情
(XXVIII) 62476 methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoate C19H23NO5S 详情 详情
(XXIX) 62477 (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoic acid C18H21NO5S 详情 详情
(XXX) 62470 (2S,3S)-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C18H19NO4S 详情 详情
(XXXI) 62478 (2S,3S)-5-[2-(dimethylamino)ethyl]-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C22H28N2O4S 详情 详情

合成路线17

The racemic precursor threo-hydroxy nitro ester (III), prepared by addition of 2-nitrothiophenol (II) to the racemic trans-glycidate (I), has been optically resolved by enantioselective lipase-catalyzed esterification of the (R,R)-isomer, producing the (R,R)-acetate (IV), while leaving unaltered the target intermediate, the (S,S)-hydroxy nitroester enantiomer (V). The racemic hydroxy nitro ester (III) has also been resolved through formation of the diastereoisomeric salts with L-lysine

参考文献 中间体
【1】 Kanerva, L.T.; Sundholm, O.; Lipase catalysis in the resolution of racemic intermediates of diltiazem synthesis in organic solvents. J Chem Soc - Perkins Trans I 1993, 13, 1385.
【2】 Senuma, M.; Shibazaki, M.; Nishimoto, S.; Shibata,K.; Okamura, K.; Date, T.; The practical resolution of (2RS,3RS)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)propionic acid, a key intermediate for diltiazem, with L-lysine. Chem Pharm Bull 1989, 37, 12, 3204.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(II) 62460 2-nitrobenzenethiol; 2-nitrophenylhydrosulfide C6H5NO2S 详情 详情
(III) 62471 methyl 2-hydroxy-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C17H17NO6S 详情 详情
(IV) 62472 methyl (2R,3R)-2-(acetyloxy)-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C19H19NO7S 详情 详情
(V) 63417 methyl (2S,3S)-2-hydroxy-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C17H17NO6S 详情 详情
Extended Information