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【结 构 式】 
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【分子编号】22146 【品名】1-isothiocyanatobenzene; phenyl isothiocyanate 【CA登记号】103-72-0 |
【 分 子 式 】C7H5NS 【 分 子 量 】135.18944 【元素组成】C 62.19% H 3.73% N 10.36% S 23.72% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of phenyl isothiocyanate (I) with 2-imino-1-methyl pyrrolidine (II) in benzene gives N-(1-methyl-2-pyrrolidinylidene)-N'-phenylthiourea (III), which is treated with iodomethane in refluxing acetone to afford methyl N-1-methyl-2-pyrrolidinylidene)-N'-phenylcarbamidothioate (IV). Finally, this compound is treated with morpholine in refluxing isopropanol.
| 【1】 Rasmussen, C.R. (Ortho-McNeil Pharmaceutical, Inc.); Nitrogen heterocyclic carboximidamide compounds. US 4211867 . |
| 【2】 Castaner, J.; Serradell, M.N.; Linogliride. Drugs Fut 1986, 11, 4, 265. |
| 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) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (II) | 27770 | 1-methyl-2-pyrrolidinimine | C5H10N2 | 详情 | 详情 | |
| (III) | 27771 | N-(1-methyl-2-pyrrolidinylidene)-N'-phenylthiourea | C12H15N3S | 详情 | 详情 | |
| (IV) | 27772 | 1-methyl-2-[[(methylsulfanyl)(phenylimino)methyl]imino]pyrrolidine | C13H17N3S | 详情 | 详情 | |
| (V) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The reductocondensation of ethyl 4-oxopiperidine-1-carboxylate (I) with methylamine by means of H2 over Pd/C in thiophene gives ethyl 4-(methylamino)piperidine-1-carboxylate (II), which is then condensed with phenyl isothiocyanate (III) in diisopropyl ether to yield the substituted thiourea (IV). The cyclization of (IV) with Br2 in refluxing CCl4 affords N-[4-(ethoxycarbonyl)piperidin-l-yl]-N methylbenzo-thiazol-2-amine (V), which is decarboxylated with refluxing 48% HBr to N-methyl-N-(4-piperidyl)benzo thiazol-2-amine (VI). Finally, this compound is condensed with 1,2-epoxy-3-(4-fluorophenoxypropane) (VII) in refluxing toluene methanol.
| 【1】 Stokbroekx, R.A.; Luyckx, M.G.M.; Janssens, F.E. (Janssen Pharmaceutica NV); Benzoxazol- and benzothiazolamine derivs.. EP 0184257; US 4861785 . |
| 【2】 Prous, J.; Castaner, J.; SABELUZOLE < Rec INN >. Drugs Fut 1988, 13, 6, 529. |
| 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) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (II) | 22145 | ethyl 4-(methylamino)-1-piperidinecarboxylate | C9H18N2O2 | 详情 | 详情 | |
| (III) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (IV) | 22147 | ethyl 4-[(anilinocarbothioyl)(methyl)amino]-1-piperidinecarboxylate | C16H23N3O2S | 详情 | 详情 | |
| (V) | 22148 | ethyl 4-[1,3-benzothiazol-2-yl(methyl)amino]-1-piperidinecarboxylate | C16H21N3O2S | 详情 | 详情 | |
| (VI) | 16742 | N-(1,3-benzothiazol-2-yl)-N-methyl-N-(4-piperidinyl)amine; N-methyl-N-(4-piperidinyl)-1,3-benzothiazol-2-amine | C13H17N3S | 详情 | 详情 | |
| (VII) | 22150 | 2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether | 18123-82-5 | C9H9FO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)A new synthesis of lubeluzole has been reported: The condensation of 3,4-difluorophenol (I) with racemic glycidol (II) by means of PPh3 and DEAD in THF gives 2-(3,4-difluorophenoxymethyl)oxirane (III), which is opened by means of Li2CuCl4 in THF yielding racemic 1-chloro-3-(3,4-difluorophenoxy)-2-propanol (IV). Racemic compound (IV) is kinetically resolved by transesterification with vinyl butyrate using Rhizomucor miehei lipase (RML) as catalyst, providing a mixture of (R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol (V) and the (S)-butyrate (VI). This mixture is easily separated by column chromatography. Finally, the (R)-alcohol (V) is condensed with N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) by means of NaHCO3 in hot DMF. The key intermediate N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) has been obtained as follows: Reductive amination of 4-oxopiperidine-1-carboxylic acid ethyl ester (VIII) with methylamine and borane/pyridine complex in methanol gives 4-(methylamino)piperidine-1-carboxylic acid ethyl ester (IX), which is condensed with isothiocyanatobenzene (X) in isopropyl ether to yield the thiourea (XI). Cyclization of compound (XI) by means of Br2 in refluxing CCl4 affords the benzothiazole derivative (V), which is finally decarboxylated by means of HBr in refluxing water, followed by treatment with NaOH.
| 【1】 Liu, H.L.; Helgehoff, B.; Berg, T.C.; Anthonsen, T.; Synthesis of the antistroke drug lubeluzole and its enantiomer. Lipase-catalyzed resolution of chiral building block. Chirality 2001, 13, 3, 135. |
| 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) | 16739 | 3,4-difluorophenol | 2713-33-9 | C6H4F2O | 详情 | 详情 |
| (II) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (III) | 47537 | 2-[(3,4-difluorophenoxy)methyl]oxirane; 3,4-difluorophenyl 2-oxiranylmethyl ether | C9H8F2O2 | 详情 | 详情 | |
| (IV) | 47534 | 1-chloro-3-(3,4-difluorophenoxy)-2-propanol | C9H9ClF2O2 | 详情 | 详情 | |
| (V) | 47535 | (1S)-2-chloro-1-[(3,4-difluorophenoxy)methyl]ethyl butyrate | C13H15ClF2O3 | 详情 | 详情 | |
| (VI) | 47536 | (2R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol | C9H9ClF2O2 | 详情 | 详情 | |
| (VII) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (VIII) | 22145 | ethyl 4-(methylamino)-1-piperidinecarboxylate | C9H18N2O2 | 详情 | 详情 | |
| (IX) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (X) | 22147 | ethyl 4-[(anilinocarbothioyl)(methyl)amino]-1-piperidinecarboxylate | C16H23N3O2S | 详情 | 详情 | |
| (XI) | 22148 | ethyl 4-[1,3-benzothiazol-2-yl(methyl)amino]-1-piperidinecarboxylate | C16H21N3O2S | 详情 | 详情 | |
| (XII) | 16742 | N-(1,3-benzothiazol-2-yl)-N-methyl-N-(4-piperidinyl)amine; N-methyl-N-(4-piperidinyl)-1,3-benzothiazol-2-amine | C13H17N3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The condensation of 3-amino-1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (I) with N-(tert-butoxycarbonyl)-L-phenylalanine (II) by means of HOBT and WSCD in DMF gives the corresponding amide as a diastereomeric mixture (IIIa-b), which is deprotected at the Boc group by treatment with HCl in ethyl acetate yielding the diastereomeric mixture of L-phenylalanine amides (IVa-b). The HPLC chromatographic separation of both diastereomers affords pure (Va) and (Vb). The desired diastereomer (Va) is treated with phenyl isothiocyanate (VI) to provide the chiral amine (R)-(VII), which is finally condensed with 3-methylphenyl isocyanate (VIII) to furnish the target urea.
| 【1】 Toyoda, T.; Adachi, M.; Sugasawa, T.; et al.; Aminohaloborane in organic synthesis. I. Specific ortho substitution reaction of anilines. J Am Chem Soc 1978, 100, 4842. |
| 【2】 Satoh, Y.; Tabuchi, S.; Mitsui, H.; Design of dual CCK-A and CCK-B receptor antagonists. Drugs Fut 1997, 22, 10, 1117. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 41214 | tert-butyl (1S)-1-benzyl-2-[[(3S)-1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]amino]-2-oxoethylcarbamate | C34H44N4O5 | 详情 | 详情 | |
| (Va) | 41216 | (2S)-2-amino-N-[(3R)-1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-3-phenylpropanamide | C29H36N4O3 | 详情 | 详情 | |
| (Vb) | 41217 | (2S)-2-amino-N-[(3S)-1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-3-phenylpropanamide | C29H36N4O3 | 详情 | 详情 | |
| (IIIb) | 41219 | tert-butyl (1S)-1-benzyl-2-[[(3R)-1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]amino]-2-oxoethylcarbamate | C34H44N4O5 | 详情 | 详情 | |
| (I) | 41213 | 3-amino-1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C20H27N3O2 | 详情 | 详情 | |
| (II) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (IV) | 41215 | (2S)-2-amino-N-[1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-3-phenylpropanamide | C29H36N4O3 | 详情 | 详情 | |
| (VI) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (VII) | 41218 | (3R)-3-amino-1-(2-cyclohexyl-2-oxoethyl)-5-ethyl-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C20H27N3O2 | 详情 | 详情 | |
| (VIII) | 18071 | m-Tolyl Isocyanate; 1-isocyanato-3-methylbenzene; 3-methylphenyl isocyanate | 621-29-4 | C8H7NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-cyclopropylethanone (IV) (obtained by bromination of acetylcyclopropane (V)) by means of NaOMe to yield the adduct (VI). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 【2】 Olesen, P.H.; Kurtzhals, P.; Bowler, A.N.; Soerensen, A.R.; Worsaae, H.; Hansen, B.F. (Novo Nordisk A/S); 2,4-Diaminothiazole derivs.. WO 0156567 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 12436 | 2-Bromo-1-cyclopropyl-1-ethanone | 69267-75-0 | C5H7BrO | 详情 | 详情 |
| (V) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (VI) | 53529 | (Z)-3-anilino-3-[(2-cyclopropyl-2-oxoethyl)sulfanyl]-2-propenenitrile | n/a | C14H14N2OS | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-pyridyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 53085 | 2-bromo-1-(3-pyridinyl)-1-ethanone | n/a | C7H6BrNO | 详情 | 详情 |
| (V) | 53539 | (Z)-3-anilino-3-{[2-oxo-2-(3-pyridinyl)ethyl]sulfanyl}-2-propenenitrile | n/a | C16H13N3OS | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-benzyloxyphenyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 【2】 Olesen, P.H.; Kurtzhals, P.; Bowler, A.N.; Soerensen, A.R.; Worsaae, H.; Hansen, B.F. (Novo Nordisk A/S); 2,4-Diaminothiazole derivs.. WO 0156567 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 53541 | 1-[3-(benzyloxy)phenyl]-2-bromo-1-ethanone | n/a | C15H13BrO2 | 详情 | 详情 |
| (IV) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (V) | 53545 | (Z)-3-({2-[3-(benzyloxy)phenyl]-2-oxoethyl}sulfanyl)-3-(4-chloroanilino)-2-propenenitrile | n/a | C24H19ClN2O2S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The reaction of 4-chloroaniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-benzyloxyphenyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 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) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 53541 | 1-[3-(benzyloxy)phenyl]-2-bromo-1-ethanone | n/a | C15H13BrO2 | 详情 | 详情 |
| (V) | 53545 | (Z)-3-({2-[3-(benzyloxy)phenyl]-2-oxoethyl}sulfanyl)-3-(4-chloroanilino)-2-propenenitrile | n/a | C24H19ClN2O2S | 详情 | 详情 |