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【结 构 式】 
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【分子编号】25182 【品名】2-aminobenzenethiol 【CA登记号】137-07-5 |
【 分 子 式 】C6H7NS 【 分 子 量 】125.19432 【元素组成】C 57.56% H 5.64% N 11.19% S 25.61% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 2-aminothiophenol (I) with diethyl benzylidenemalonate (II) by heating at 90 C gives diethyl 2-(2-aminophenylthio)-2-phenylethane-1,1-dicarboxylate (III), which is cyclized by heating at 180 C with triethylamine hydrochloride yielding 2,3-dihydro-3-ethoxycarbonyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (IV). The reduction of (IV) with LiAlH4 in THF affords 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (V), which by reaction with SOCl2 in refluxing benzene is converted into 2,3-dihydro-3-chloromethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (VII). Finally, this compound is treated with N-methylpiperazine at reflux temperature, and acidified with HCl. An alternative way is the reaction of (V) with methanesulfonyl chloride in pyridine affording 2,3-dihydro-3-methanesulfonyloxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (VI), which is then treated with N-methylpiperazine and HCl as before.
| 【1】 Izumi, K.; et al.; FR 2416890 . |
| 【2】 Hillier, K.; Castaner, J.; BTM-1042. Drugs Fut 1981, 6, 9, 534. |
| 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) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (I) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (II) | 37482 | diethyl 2-benzylidenemalonate | 5292-53-5 | C14H16O4 | 详情 | 详情 |
| (III) | 37483 | diethyl 2-[[(2-aminophenyl)sulfanyl](phenyl)methyl]malonate | C20H23NO4S | 详情 | 详情 | |
| (IV) | 37484 | ethyl (2R,3R)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-carboxylate | C18H17NO3S | 详情 | 详情 | |
| (V) | 37485 | (2R,3S)-3-(hydroxymethyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO2S | 详情 | 详情 | |
| (VI) | 37486 | (2R,3S)-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C19H21NO2S2 | 详情 | 详情 | |
| (VII) | 37487 | (2R,3S)-3-(chloromethyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H14ClNOS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)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)
| 【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3
该中间体在本合成路线中的序号：(VII)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
| 【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
该中间体在本合成路线中的序号：(VII)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
| 【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5
该中间体在本合成路线中的序号：(VIII)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)
| 【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6
该中间体在本合成路线中的序号：(VII)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)
| 【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7
该中间体在本合成路线中的序号：(VII)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)
| 【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8
该中间体在本合成路线中的序号：(X)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
| 【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9
该中间体在本合成路线中的序号：(X)Addition of Grignard reagent (II) to N-(4-formylphenyl)acetamide (I) produced carbinol (III). After conversion of (III) to mesylate (IV), displacement with 1,2,4-triazole (V) afforded triazolyl derivative (VI). Acid hydrolysis of the acetamido group of (VI) furnished aniline (VII). Treatment of aniline (VII) with carbon disulfide and NaOH, followed by methylation with iodomethane, gave the bis(methylthio)methylene derivative (VIII). Alternatively, aniline (VII) was converted to isothiocyanate (IX) by reaction with thiophosgene. The title benzothiazole was finally obtained by condensation of 2-aminobenzenethiol (X) with either (VIII) or (IX).
| 【1】 Venet, M.G.; Mabire, D.J.-P.; Lacrampe, J.F.A.; Sanz, G.C. (Janssen Pharmaceutica NV); N-[4-(heteroarylmethyl)phenyl]-heteroarylamines. EP 0907650; JP 2000503670; US 6124330; WO 9749704 . |
| 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) | 42212 | N-(4-formylphenyl)acetamide | 122-85-0 | C9H9NO2 | 详情 | 详情 |
| (II) | 42213 | bromo(1-ethylpropyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (III) | 42214 | N-[4-(2-ethyl-1-hydroxybutyl)phenyl]acetamide | C14H21NO2 | 详情 | 详情 | |
| (IV) | 42215 | 1-[4-(acetamido)phenyl]-2-ethylbutyl methanesulfonate | C15H23NO4S | 详情 | 详情 | |
| (V) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (VI) | 42216 | N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]acetamide | C16H22N4O | 详情 | 详情 | |
| (VII) | 42217 | 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]aniline; 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenylamine | C14H20N4 | 详情 | 详情 | |
| (VIII) | 42218 | 1-[1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-ethylbutyl]-1H-1,2,4-triazole | C17H24N4S2 | 详情 | 详情 | |
| (IX) | 42219 | 1-[2-ethyl-1-(4-isothiocyanatophenyl)butyl]-1H-1,2,4-triazole; 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl isothiocyanate | C15H18N4S | 详情 | 详情 | |
| (X) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)Benzothiazin (III) was prepared by condensation of 2-aminothiophenol (I) with ethyl 4-bromoacetoacetate (II). Subsequent reduction of (III) with NaBH3CN provided (IV), which was brominated using N-bromosuccinimide to afford (V). This was coupled with ethyl oxalyl chloride to give amide (VI). Nitration of (VI) was then performed with HNO3 in H2SO4 at -10 C. Further reduction of the nitro group of (VII) with concomitant cyclization produced the tricyclic compound (VIII). After resolution by chiral preparative HPLC, the required (R)-enantiomer was hydrolyzed with NaOH to afford carboxylic acid (IX). This compound was finally isolated as the sodium salt upon treatment with aqueous NaHCO3, followed by lyophilization.
| 【1】 Moretti, R.; Zimmermann, K. (Novartis AG); Quinoxaline-2,3-diones with an oxa or thiaheterocyclic fused ring. CA 2157231; EP 0705835; JP 1996109185 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 | |
| (I) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (III) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (IV) | 25184 | ethyl 2-[2H-1,4-benzothiazin-3(4H)-ylidene]acetate | C12H13NO2S | 详情 | 详情 | |
| (IV) | 25185 | ethyl 2-(3,4-dihydro-2H-1,4-benzothiazin-3-yl)acetate | C12H15NO2S | 详情 | 详情 | |
| (V) | 25186 | ethyl 2-(7-bromo-3,4-dihydro-2H-1,4-benzothiazin-3-yl)acetate | C12H14BrNO2S | 详情 | 详情 | |
| (VI) | 25187 | ethyl 2-[7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-2-oxoacetate | C16H18BrNO5S | 详情 | 详情 | |
| (VII) | 25188 | ethyl 2-[7-bromo-3-(2-ethoxy-2-oxoethyl)-5-nitro-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-2-oxoacetate | C16H17BrN2O7S | 详情 | 详情 | |
| (VIII) | 25189 | ethyl 2-(9-bromo-5,6-dioxo-2,3,6,7-tetrahydro-5H-[1,4]thiazino[4,3,2-de]quinoxalin-3-yl)acetate | C14H13BrN2O4S | 详情 | 详情 | |
| (IX) | 25190 | 2-[(3R)-9-bromo-5,6-dioxo-2,3,6,7-tetrahydro-5H-[1,4]thiazino[4,3,2-de]quinoxalin-3-yl]acetic acid | C12H9BrN2O4S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(X)Friedel-Crafts acylation of acetanilide (I) with 2-chloropropionyl chloride (II) in the presence of AlCl3 provided ketone (III). The chlorine atom of (III) was then displaced with dimethylamine to afford amino ketone (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. Treatment of alcohol (V) with carbonyl diimidazole furnished the imidazolyl derivative (VI). The acetamido group of (VI) was then hydrolyzed with 3N HCl to give aniline (VII). This compound was converted to isothiocyanate (VIII) by treatment with thiophosgene and NaOH. Alternatively, aniline (VII) was treated with carbon disulfide and NaOH and then with iodomethane to give the bis(methylthio)methyleneamino derivative (IX). The condensation of either (VIII) or (IX) with 2-aminothiophenol (X) produced the target benzothiazole (XI) as a mixture of isomers. Then, separation of the diastereoisomers by column chromatography, followed by resolution by chiral HPLC, furnished the title (S,S)-isomer.
| 【1】 Venet, M.; Van Wauwe, J.; Mabire, D.; Sanz, G.; Poignet, H.; Wouters, J.; Synthesis of R116010, a retinoic acid (RA) metabolism inhibitor with antitumoral effects. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-60. |
| 【2】 Venet, M.G.; Mabire, D.J.-P.; Lacrampe, J.F.A.; Sanz, G.C. (Janssen Pharmaceutica NV); N-[4-(heteroarylmethyl)phenyl]-heteroarylamines. EP 0907650; JP 2000503670; US 6124330; WO 9749704 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 46351 | N-[4-[(1R,2S)-2-(dimethylamino)-1-hydroxypropyl]phenyl]acetamide | C13H20N2O2 | 详情 | 详情 | |
| (Vb) | 46352 | N-[4-[(1S,2S)-2-(dimethylamino)-1-hydroxypropyl]phenyl]acetamide | C13H20N2O2 | 详情 | 详情 | |
| (VIa) | 46353 | N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]acetamide | C16H22N4O | 详情 | 详情 | |
| (VIb) | 46354 | N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]acetamide | C16H22N4O | 详情 | 详情 | |
| (VIIa) | 46355 | N-[(1S,2R)-2-(4-aminophenyl)-2-(1H-imidazol-1-yl)-1-methylethyl]-N,N-dimethylamine; 4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]aniline | C14H20N4 | 详情 | 详情 | |
| (VIIb) | 46356 | N-[(1S,2S)-2-(4-aminophenyl)-2-(1H-imidazol-1-yl)-1-methylethyl]-N,N-dimethylamine; 4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]aniline | C14H20N4 | 详情 | 详情 | |
| (VIIIa) | 46357 | (1R,2S)-1-(1H-imidazol-1-yl)-1-(4-isothiocyanatophenyl)-N,N-dimethyl-2-propanamine; N-[(1S,2R)-2-(1H-imidazol-1-yl)-2-(4-isothiocyanatophenyl)-1-methylethyl]-N,N-dimethylamine | C15H18N4S | 详情 | 详情 | |
| (VIIIb) | 46358 | N-[(1S,2S)-2-(1H-imidazol-1-yl)-2-(4-isothiocyanatophenyl)-1-methylethyl]-N,N-dimethylamine; (1S,2S)-1-(1H-imidazol-1-yl)-1-(4-isothiocyanatophenyl)-N,N-dimethyl-2-propanamine | C15H18N4S | 详情 | 详情 | |
| (IXa) | 46359 | 1-[(1R,2S)-1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-(dimethylamino)propyl]-1H-imidazole | C17H24N4S2 | 详情 | 详情 | |
| (IXb) | 46360 | 1-[(1S,2S)-1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-(dimethylamino)propyl]-1H-imidazole | C17H24N4S2 | 详情 | 详情 | |
| (XIa) | 46361 | N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-1,3-benzothiazol-2-amine; N-(1,3-benzothiazol-2-yl)-N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]amine | C21H23N5S | 详情 | 详情 | |
| (XIb) | 46362 | N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-1,3-benzothiazol-2-amine; N-(1,3-benzothiazol-2-yl)-N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]amine | C21H23N5S | 详情 | 详情 | |
| (I) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (II) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (III) | 46349 | N-[4-(2-chloropropanoyl)phenyl]acetamide | C11H12ClNO2 | 详情 | 详情 | |
| (IV) | 46350 | N-[4-[2-(dimethylamino)propanoyl]phenyl]acetamide | C13H18N2O2 | 详情 | 详情 | |
| (X) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(X)In an alternative procedure, 2-aminothiophenol (X) was condensed with phenyl isothiocyanate (XII) to produce N-phenyl-2-aminobenzothiazole (XIII). Subsequent Friedel-Crafts acylation of (XIII) with acid chloride (II) gave chloro ketone (XIV), which was converted to amino ketone (XV) upon treatment with dimethylamine. After ketone (XV) reduction with NaBH4, the resulting amino alcohol (XVI) was treated with carbonyl diimidazole, and the mixture of isomers was chromatographically separated as above.
| 【1】 Venet, M.; Van Wauwe, J.; Mabire, D.; Sanz, G.; Poignet, H.; Wouters, J.; Synthesis of R116010, a retinoic acid (RA) metabolism inhibitor with antitumoral effects. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIa) | 46367 | (1R,2S)-1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanol | C18H21N3OS | 详情 | 详情 | |
| (XVIb) | 46368 | (1S,2S)-1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanol | C18H21N3OS | 详情 | 详情 | |
| (X) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (XI) | 46363 | benzenesulfenyl cyanide | C7H5NS | 详情 | 详情 | |
| (XII) | 46364 | N-(1,3-benzothiazol-2-yl)-N-phenylamine; N-phenyl-1,3-benzothiazol-2-amine | C13H10N2S | 详情 | 详情 | |
| (XIII) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (XIV) | 46365 | 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-chloro-1-propanone | C16H13ClN2OS | 详情 | 详情 | |
| (XV) | 46366 | 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanone | C18H19N3OS | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)Condensation of substituted aniline (I) with acrylic acid (II) in toluene affords bicyclic derivative (III), whose carbonyl is reduced by means of Red-Al in toluene to yield compound (IV). Conversion of (IV) into bicyclic hydrazine (V) is then performed by treatment with NaNO2 and HOAc followed by reduction of the resulting diazo derivative with LiAlH4 in THF. Derivative (V) is then subjected to a Fisher indole cyclization process by reaction with ketone (VI) and HCl in iPrOH to provide compound (VII), which is then regioselectively reduced with NaCNBH3 in TFA to give tetracyclic indoline (VIII). N-Protection of (VIII) with Boc2O and NaOH affords Boc protected derivative (IX), which is then selectively brominated by means of NBS in DMF to yield bromo derivative (X). Finally, the desired compound is obtained by a Suzuki cross-coupling reaction between (X) and boronic acid (XI) catalyzed by Pd(PPh3)4, followed by Boc removal with TFA in CH2Cl2.
| 【1】 Robichaud, A.J.; Chen, W.; McClung, C.; et al.; Synthesis and biological evaluation of novel, selective 5-HT2C receptor agonists for the treatment of obesity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 105. |
| 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) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (II) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 48910 | 2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one | C9H9NOS | 详情 | 详情 | |
| (IV) | 22617 | 2,3,4,5-tetrahydro-1,5-benzothiazepine | C9H11NS | 详情 | 详情 | |
| (V) | 48146 | 3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine | C9H12N2S | 详情 | 详情 | |
| (VI) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (VII) | 48147 | 6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H16N2S | 详情 | 详情 | |
| (VIII) | 48150 | (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H18N2S | 详情 | 详情 | |
| (IX) | 48149 | tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate | C19H26N2O2S | 详情 | 详情 | |
| (X) | 48911 | tert-butyl (8aS,12aR)-2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate | C19H25BrN2O2S | 详情 | 详情 | |
| (XI) | 48912 | 2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid | 68716-47-2 | C6H5BCl2O2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(I)Condensation of 2-aminothiophenol (I) with 4-nitrobenzoyl chloride (II) produces the benzothiazole (III). Reduction of the nitro group of (III) by means of SnCl2 in refluxing EtOH yields aniline (IV). Then, alkylation of (IV) with 11C-labeled iodomethane gives rise to the target 11C-methylated aniline.
| 【1】 Mathis, C.A.; et al.; A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 2002, 12, 3, 295. |
| 【2】 Wang, Y.; Klunk, W.E.; Mathis, C.A. Jr. (University of Pittsburgh); Thioflavin derivs. for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition. WO 0216333 . |
| 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) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (II) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (III) | 58508 | 2-(4-nitrophenyl)-1,3-benzothiazole | C13H8N2O2S | 详情 | 详情 | |
| (IV) | 58509 | 4-(1,3-benzothiazol-2-yl)aniline; 4-(1,3-benzothiazol-2-yl)phenylamine | C13H10N2S | 详情 | 详情 |