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【结 构 式】

【分子编号】10151

【品名】Ethyleneimine; Aziridine; Azirane

【CA登记号】151-56-4

【 分 子 式 】C2H5N

【 分 子 量 】43.06844

【元素组成】C 55.78% H 11.7% N 32.52%
与该中间体有关的原料药合成路线共 20 条
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18合成路线19合成路线20

合成路线1

该中间体在本合成路线中的序号：(C)

The alkylation of p-chloroaniline (V) as before yields N-(2,2,2-trifluoroethyl)aniline (VI), which is then condensed with aziridine (C) affording the substituted aniline (VII). The benzoylation of (VII) with 2-fluorobenzoyl chloride (D) yields the amide (VIII), which is cyclized with P2O5 in refluxing POCl3 giving 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine (IX). This compound is oxidized with RuO4 in CCl4 to give 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (I), which by reaction with P2S5 in refluxing dioxane gives the target compound.

参考文献 中间体
合成目标
【1】 Steinman, M.; Benzodiazepines and the process for their manufacture. DE 2138773; ES 393953; FR 2102114; GB 1345938 .
【2】 Steinman, M.; 1-Polyfluoroalkyl-1,4-benzodiazepin-2-thiones for effecting tranquilization, sedation and treating colvulsions. US 3920818 .
【3】 Castaner, J.; Thorpe, P.; Quazepam. Drugs Fut 1978, 3, 2, 139.
【4】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 19551 2-Fluorobenzoyl chloride 393-52-2 C7H4ClFO 详情 详情
(A) 33474 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate 23199-56-6 C3H2Cl3F3O3S 详情 详情
(I) 33471 7-Chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one C17H11ClF4N2O 详情 详情
(V) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(VI) 33475 N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline C8H7ClF3N 详情 详情
(VII) 33476 N(1)-(4-chlorophenyl)-N(1)-(2,2,2-trifluoroethyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine C10H12ClF3N2 详情 详情
(VIII) 33477 N-[2-[4-chloro(2,2,2-trifluoroethyl)anilino]ethyl]-2-fluorobenzamide C17H15ClF4N2O 详情 详情
(IX) 33478 7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine; 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine C17H13ClF4N2 详情 详情
(C) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

By reaction of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (I) with ethyleneimine (II) in refluxing CHCl3.

参考文献 中间体
合成目标
【1】 Scolastico, C.; Tronconi, G.; DE 2711149 .
【2】 de Angelis, L.; Pirinixil. Drugs Fut 1979, 4, 4, 273.
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) 39473 2-[[4-chloro-6-(2,3-dimethylanilino)-2-pyrimidinyl]sulfanyl]acetic acid 50892-23-4 C14H14ClN3O2S 详情 详情
(II) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The reaction of chloranil (I) with ethyl carbamate (II) by means of Na in dry benzene gives 2,5-dichloro-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone (III), which is then condensed with aziridine (IV) by means of triethylamine in THF.

参考文献 中间体
合成目标
【1】 Driscoll, J.S.; et al.; Structure-antitumor activity relationships among quinone derivatives. Cancer Chemother Rep 1974, 4, 2, 1.
【2】 Zubrod, C.G.; Rall, D.P.; Anu Rev Pharmacol 1962, 2, 109.
【3】 Kahn, A.H.; Driscoll, J.S.; Potential central nervous system antitumor agents. Azirinylbenzoquinones. 1. J Med Chem 1976, 19, 2, 313-317.
【4】 Driscoll, J.S.; et al. (US Department of Health & Human Services); Aziridinyl quinone anti-transplanted tumor agents. US 4146622 .
【5】 Cabanillas, F.; Blancafort, P.; Serradell, M.N.; Castaner, J.; AZQ. Drugs Fut 1981, 6, 6, 338.
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) 21891 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil 118-75-2 C6Cl4O2 详情 详情
(II) 24199 Ethyl carbamate; Urethane 51-79-6 C3H7NO2 详情 详情
(III) 32193 2,5-Dichloro-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone; Ethyl 2,5-dichloro-4-[(ethoxycarbonyl)amino]-3,6-dioxo-1,4-cyclohexadien-1-ylcarbamate C12H12Cl2N2O6 详情 详情
(IV) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

By reaction of 1,3,3,5,5-pentachloro-1-thia-2,4,6-triaza-3,5-diphosphorine-1-oxide (I) with aziridine (II) in ether.

参考文献 中间体
合成目标
【1】 Van der Huizen, A.A.; Sournies, F.; Labarre, J.F.; Van der Grampel, J.C.; Wiedijk, D.; Jekel, A.P.; Derivatives of cis-NPCl2(NSOCl)2 and (NPCl2)2 NSOCl. Part XVI. The preparation of some aziridino (ethyleneimino) derivatives of (NPCl2)2 NSOX (X=F,Az,Ph) with a potential anticancer activity. Inorg Chim Acta 1981, 53, 4, 169-170.
【2】 Labarre, J.F.; Sournies, F.; Van der Grampel, J.; Van der Huizen, A. (ANVAR (Agence Natl. Valor. Rech.)); Inorganocyclic cpds. usable as medicaments and a process for their preparation. EP 0022407 .
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hopkins, S.J.; SOAz. Drugs Fut 1983, 8, 7, 605.
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) 36151 1,3,3,5,5-pentachloro-1lambda(6),2,4,6,3lambda(5),5lambda(5)-thiatriazadiphosphinin-1-one Cl5N3OP2S 详情 详情
(II) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VII)

[2H]-Labeled RSU-1069 is synthesized as follows: The condensation of 2-nitroimidazole (I) with 3-chloro-1,2-epoxypropane (II) gives 1-(3-chloro-2-hydroxypropyl)-2-nitroimidazole (III), which is oxidized with CrO3 - H2SO4 in acetone yielding 1-(3-chloro-2-oxopropyl)-2-nitroimidazole (IV). The reduction of (IV) with NaB[2H]4 in ethanol affords 1-(3-chloro-2-hydroxy-2(2H)-propyl)-2-nitroimidazole (V), which is cyclized with NaOH to the corresponding labeled epoxide (VI). Finally, this compound is condensed with aziridine (VII) by means of triethylamine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Webb, P.; Threadgill, M.D.; Labelled compounds of interest as antitumour agents. Part II (1). Synthesis of 2H and 3H isotopomers of RSU 1069 and Ro 03-8799 (pimonidazole). J Label Compd Radiopharm 1990, 28, 3, 257.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III),(V) 10147 1-Chloro-3-(2-nitro-1H-imidazol-1-yl)-2-propanol C6H8ClN3O3 详情 详情
(I) 10145 2-Nitro-1H-imidazole; 2-Nitroimidazole 527-73-1 C3H3N3O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 10148 1-Chloro-3-(2-nitro-1H-imidazol-1-yl)acetone C6H6ClN3O3 详情 详情
(V) 44588 1-chloro-3-(2-nitro-1H-imidazol-1-yl)-2-propanol C6H8ClN3O3 详情 详情
(VI) 10150 2-Nitro-1-(2-oxiranylmethyl)-1H-imidazole C6H7N3O3 详情 详情
(VI) 44589 2-nitro-1-(2-oxiranylmethyl)-1H-imidazole C6H7N3O3 详情 详情
(VII) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

By reaction of 1-(2,3-epoxypropyl)-2-nitroimidazole (I) with aziridine (II) in refluxing methanol.

参考文献 中间体
合成目标
【1】 Foster, J.L.; Deutsh, G.; Parnell, M.; McFadzean, J.A.; Human studies with "high dose" metronidazole; a non-toxic radiosensitizer of hypoxic cells. Brit J Cancer 1984, 49, 1, 571.
【2】 Ahmed, I.; Adams, G.E.; Stratford, I.J. (National Research Development Corp.); Aziridino containing nitro imidazoles and pharmaceutical compositions. EP 0095906; GB 2123816; JP 58225086; US 4596817; US 4631289; US 4757148 .
【3】 Hopkins, S.J.; Castaner, J.; RSU-1069. Drugs Fut 1986, 11, 6, 467.
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) 10150 2-Nitro-1-(2-oxiranylmethyl)-1H-imidazole C6H7N3O3 详情 详情
(II) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线7

该中间体在本合成路线中的序号：(III)

Title compound can be prepared by two different ways: 1) The reaction of 1,4,7,10-tetraoxa-13-azacyclopentandecane (I) with phosphoryl chloride in the presence of triethylamine in diethyl ether gives 13-(dichlorophosphoryl)-1,4,7,10-tetraoxa-13-azacyclopentandecane (II), which is subsequently reacted with aziridine (III) in the presence of triethylamine to give azacrown-TEPA. 2) The reaction of the aziridine (III) with phosphoryl chloride in the presence of triethylamine in diethyl ether gives bis(1-aziridinyl)chlorophosphine oxide (IV), which is subsequently reacted with 1,4,7,10-tetraoxa-13-azacyclopentandecane (I) in the presence of triethylamine to afford azacrown-TEPA.

参考文献 中间体
合成目标
【1】 Okahara, M.; Nakatsuji, Y.; Maeda, H.; Facile synthesis of monoaza crown ethers. J Med Chem 1981, II, 471-472.
【2】 Lukszo, J.; Sosnovsky, G.; Azacrown-TEPA. Drugs Fut 1985, 10, 4, 275.
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) 29102 1,4,7,10-tetraoxa-13-azacyclopentadecane 66943-05-3 C10H21NO4 详情 详情
(II) 29103 1,4,7,10-tetraoxa-13-azacyclopentadecan-13-ylphosphonic dichloride C10H20Cl2NO5P 详情 详情
(III) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(IV) 29104 di(1-aziridinyl)phosphinic chloride C4H8ClN2OP 详情 详情

合成路线8

该中间体在本合成路线中的序号：(C)

The reaction of 4-chloro-N-(2,2,2-trifluoroethyl)aniline (V) with ethyleneimine (C) by means of AlCl3 in benzene affords the N-(2-aminoethyl) compound (VI), which is benzoylated with benzoyl chloride (D) as usual yielding the benzamide (VII). Compound (VII) is cyclized with P2O5 in POCl3 giving 7-chloro-1,2-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine (VIII), which is finally oxidized with RuO4.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(V) 33475 N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline C8H7ClF3N 详情 详情
(VI) 33476 N(1)-(4-chlorophenyl)-N(1)-(2,2,2-trifluoroethyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine C10H12ClF3N2 详情 详情
(VII) 33850 N-[2-[4-chloro(2,2,2-trifluoroethyl)anilino]ethyl]benzamide C17H16ClF3N2O 详情 详情
(VIII) 33851 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine C17H14ClF3N2 详情 详情
(C) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

The cyclization of piperidine-2-carboxylic acid ethyl ester (I) with aziridine (II) in ethanol gives perhydropyrido[1,2-a]pyrazin-1-one (III), which is reduced with LiAlH4 to yield perhydropyrido[1,2-a]pyrazine (IV). The reaction of (IV) with NaNO2/HCl, followed by reduction with LiAlH4, affords perhydropyrido[1,2-a]pyrazin-2-amine (V), which is finally condensed with rifamicin SV-3-carbaldehyde (VI).

参考文献 中间体
合成目标
【1】 Hauffe, S.; Tosch, W.; Batt, E.; Ashtekar, D.R.; Costa-Pereira, R.; Vischer, W.; Traxler, P.; Degen, P.; Zak, O.; Imhof, P.; Gowrishankar, R.; 3-Formylrifamycin SV-hydrazones with diazabicycloalkyl side-chains: New rifamycins aganist tuberculosis with long plasma half-lives. 27th Intersci Conf Antimicrob Agents Chemother 1987, Abst 278.
【2】 Ashtekar, D.R.; Vischer, W.; Kump, W.; Costa-Pereira, R.; Traxler, P.; Subrahmanyam, D.; Gowrishankar, R.; Antitubercular activity in vitro and in vivo of new long-acting rifamycin derivatives. Bull Intl Union Tuberc 1986, 61, 3, 8.
【3】 Traxler, P. (Novartis Corp.); Novel polycyclic hydrazones of rifamycins, their manufacture, and their pharmaceutical compsns. for treating tuberculosis. US 4681938 .
【4】 Traxler, P.; Vischer, W.; Zak, O.; New Rifamycins. Drugs Fut 1988, 13, 9, 845.
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) 43693 ethyl 2-piperidinecarboxylate 15862-72-3 C8H15NO2 详情 详情
(II) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(III) 43694 hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one C8H14N2O 详情 详情
(IV) 43695 octahydro-2H-pyrido[1,2-a]pyrazine C8H16N2 详情 详情
(V) 43696 octahydro-2H-pyrido[1,2-a]pyrazin-2-ylamine; octahydro-2H-pyrido[1,2-a]pyrazin-2-amine C8H17N3 详情 详情
(VI) 43692 26-formyl-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.1(4,7).0(5,28)]triaconta-1(28),1(29),2,4,9,19,21,25,27-nonaen-13-yl acetate C38H47NO13 详情 详情

合成路线10

该中间体在本合成路线中的序号：(A)

Ethyleneimine is reacted with tetrafluoro-1.4-benzoquinone (I) in the cold to form 2,5-diaziridinyl-3,6-difluoro-1-4-benzoquinone (II). The reaction with ethanolamine at room temperature results in BZQ, which is recrystallized from ethanol.

参考文献 中间体
合成目标
【1】 Chou, F.; et al.; Potential central nervous system antitumor agents. Aziridinylbenzoquinones. J Med Chem 1976, 19, 11, 1302.
【2】 Bosanquet, A.G.; BZQ. Drugs Fut 1986, 11, 1, 12.
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) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(B) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(I) 24122 2,3,5,6-tetrafluorobenzo-1,4-quinone 527-21-9 C6F4O2 详情 详情
(II) 24123 2,5-di(1-aziridinyl)-3,6-difluorobenzo-1,4-quinone C10H8F2N2O2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

The cyclization of 5-ethylpiperidine-2-carboxylic acid ethyl ester (I) with aziridine (II) in ethanol gives 7-ethylperhydropyrido[1,2-a]pyrazin-1-one (III), which is reduced with LiAlH4 to yield 7-ethylperhydropyrido[1,2-a]pyrazine (IV). The reaction of (IV) with NaNO2/HCl, followed by reduction with LiAlH4, affords 7-ethylperhydropyrido[1,2-a]pyrazin-2-amine (V), which is finally condensed with rifamicin SV-3-carbaldehyde (VI).

参考文献 中间体
合成目标
【1】 Hauffe, S.; Tosch, W.; Batt, E.; Ashtekar, D.R.; Costa-Pereira, R.; Vischer, W.; Traxler, P.; Degen, P.; Zak, O.; Imhof, P.; Gowrishankar, R.; 3-Formylrifamycin SV-hydrazones with diazabicycloalkyl side-chains: New rifamycins aganist tuberculosis with long plasma half-lives. 27th Intersci Conf Antimicrob Agents Chemother 1987, Abst 278.
【2】 Traxler, P. (Novartis Corp.); Novel polycyclic hydrazones of rifamycins, their manufacture, and their pharmaceutical compsns. for treating tuberculosis. US 4681938 .
【3】 Traxler, P.; Vischer, W.; Zak, O.; New Rifamycins. Drugs Fut 1988, 13, 9, 845.
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) 43688 ethyl 5-ethyl-2-piperidinecarboxylate C10H19NO2 详情 详情
(II) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(III) 43689 7-ethylhexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one C10H18N2O 详情 详情
(IV) 43690 7-ethyloctahydro-2H-pyrido[1,2-a]pyrazine C10H20N2 详情 详情
(V) 43691 7-ethyloctahydro-2H-pyrido[1,2-a]pyrazin-2-amine; 7-ethyloctahydro-2H-pyrido[1,2-a]pyrazin-2-ylamine C10H21N3 详情 详情
(VI) 43692 26-formyl-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.1(4,7).0(5,28)]triaconta-1(28),1(29),2,4,9,19,21,25,27-nonaen-13-yl acetate C38H47NO13 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

The condensation of aziridine (I) with methyl 4-hydroxybenzoate (II) in refluxing chloroform gives methyl 4-(2-aminoethoxy)benzoate (III), which is acylated with 4-isopropylbenzoyl chloride by means of K2CO3 in chloroform yielding methyl 4-[2-(4-isopropylbenzamido)ethoxy]benzoate (IV). Finally, this compound is hydrolyzed with NaOH in refluxing water.

参考文献 中间体
合成目标
【1】 Yoshikuni, Y.; Choaki, S.; Ozaki, T.; Yoshida, H. (Nippon Shinyaku Co., Ltd.); Benzoic acid derivs. CH 674204; DE 3718765; FR 2600059; GB 2191487; JP 1987292754; JP 1988159359; US 4831055 .
【2】 Prous, J.; Castaner, J.; NS-1. Drugs Fut 1990, 15, 7, 682.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
41310 4-isopropylbenzoyl chloride C10H11ClO 详情 详情
(I) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(II) 10251 methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate 99-76-3 C8H8O3 详情 详情
(III) 12457 methyl 4-(2-aminoethoxy)benzoate C10H13NO3 详情 详情
(IV) 12458 methyl 4-[2-[(4-isopropylbenzoyl)amino]ethoxy]benzoate C20H23NO4 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XXIII)

1) The nitrosation of 3-chlorophenol (I) with NaNO2 and H2SO4 in water gives 3-chloro-4-nitrophenol (III), which is methylated with SO4(Me)2 and NaH in THF to yield 3-chloro-4-nitroanisole (IV). The condensation of (IV) with ethyl cyanoacetate (V) by means of NaH in DMF affords ethyl 2-(5-methoxy-2-nitrophenyl)cyanoacetate (VI), which is submitted to ethanolysis with ethanol/HCl affording the malonic ester derivative (VII). The hydrogenation of (VII) with H2 over PtO2 in toluene/ethanol gives the corresponding amino derivative (VIII), which is condensed with methyl 3-formylacrylate (IX) in ethanol yielding the intermediate imine (X). This imine (X), without isolation, is cyclized with zinc acetate in methanol affording 3-[3,3-bis(ethoxycarbonyl)-5-methoxy-2,3-dihydro-1H-indol-2-yl]acrylic acid methyl ester (XI), which is acetylated with acetic anhydride to the N-acetyl derivative (XII). The decarboxylative hydrolysis of (XII) with KOH in ethanol gives 3-(1-acetyl-3-carboxy-5-methoxy-2,3-dihydro-1H-indol-2-yl)acrylic acid (XIII), which is converted into its dimethyl ester (XIV) with SO4(Me)2 and K2CO3. The dehydrogenation of (XIV) with dichlorodicyanobenzoquinone (DDQ) in refluxing toluene yields 3-[1-acetyl-5-methoxy-3-(methoxycarbonyl)-1H-indol-2-yl]acrylic acid methyl ester (XV), which is deacetylated to (XVI) by column chromatography over basic alumina in dichloromethane/acetone. The nitration of (XVI) with fuming nitric acid in acetic acid affords the 4-nitro derivative (XVII), which is methylated with NaH and methyl iodide to the N-methyl derivative (XVIII). The reduction of (XVIII) with Sn and 3N HCl in ethanol/water yields the corresponding 4-amino derivative (XIX), which is oxidized with Fremy's salt (nitrodisulfonic acid potassium salt) to afford 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4,7-dioxo-4,7-dihydro-1H-indo l -2-yl]acrylic acid methyl ester (XX). The reduction of (XX) with Na2S2O4 in CHCl3/ethanol/water gives the corresponding hydroquinone (XXI), which is first reduced with DIBAL (diisobutylaluminum hydride) in toluene/dichloromethane and then oxidized again with FeCl3 to afford 3-(hydroxymethyl)-2-(3-hydroxy-1-propenyl)-5-methoxy-1-methyl-4,7-dihydro-1H-indole-4,7-dione (XXII). Finally, this compound is treated with aziridine (XXIII) in hot methanol.

参考文献 中间体
合成目标
【1】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143.
【2】 Oostveen, E.A.; Speckamp, W.N.; Mitomycin analogues I. Indoloquinones as (potential) bisalkylating agents. Tetrahedron 1987, 43, 255-62.
【3】 Speckamp, W.N.; Oostveen, E.A. (University of Amsterdam); Indoloquinone cpds. JP 1989502906; US 5079257; WO 8706227 .
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) 12597 3-Chlorophenol; m-Chlorophenol 108-43-0 C6H5ClO 详情 详情
(II) 12598 3-Chloro-4-nitrosophenol C6H4ClNO2 详情 详情
(III) 12599 3-Chloro-4-nitrophenol 491-11-2 C6H4ClNO3 详情 详情
(IV) 12600 3-Chloro-4-nitrophenyl methyl ether; 2-Chloro-4-methoxy-1-nitrobenzene; 3-Chloro-4-nitroanisole 28987-59-9 C7H6ClNO3 详情 详情
(V) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(VI) 12602 ethyl 2-cyano-2-(5-methoxy-2-nitrophenyl)acetate C12H12N2O5 详情 详情
(VII) 12603 diethyl 2-(5-methoxy-2-nitrophenyl)malonate C14H17NO7 详情 详情
(VIII) 12604 diethyl 2-(2-amino-5-methoxyphenyl)malonate C14H19NO5 详情 详情
(IX) 12605 methyl (E)-4-oxo-2-butenoate 7327-99-3 C5H6O3 详情 详情
(X) 12606 diethyl 2-(5-methoxy-2-[[(E,2E)-4-methoxy-4-oxo-2-butenylidene]amino]phenyl)malonate C19H23NO7 详情 详情
(XI) 12607 diethyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1,2-dihydro-3H-indole-3,3-dicarboxylate C19H23NO7 详情 详情
(XII) 12608 diethyl 1-acetyl-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1,2-dihydro-3H-indole-3,3-dicarboxylate C21H25NO8 详情 详情
(XIII) 12609 1-Acetyl-2-[(E)-2-carboxyethenyl]-5-methoxy-3-indolinecarboxylic acid C15H15NO6 详情 详情
(XIV) 12610 methyl 1-acetyl-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-3-indolinecarboxylate C17H19NO6 详情 详情
(XV) 12611 methyl 1-acetyl-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1H-indole-3-carboxylate C17H17NO6 详情 详情
(XVI) 12612 methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1H-indole-3-carboxylate C15H15NO5 详情 详情
(XVII) 12613 methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-nitro-1H-indole-3-carboxylate C15H14N2O7 详情 详情
(XVIII) 12614 methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-4-nitro-1H-indole-3-carboxylate C16H16N2O7 详情 详情
(XIX) 12615 methyl 4-amino-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-1H-indole-3-carboxylate C16H18N2O5 详情 详情
(XX) 12616 methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-3-carboxylate C16H15NO7 详情 详情
(XXI) 12617 methyl 4,7-dihydroxy-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-1H-indole-3-carboxylate C16H17NO7 详情 详情
(XXII) 12618 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione C14H15NO5 详情 详情
(XXIII) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XXIII)

2) The esterification of 2-hydroxy-3-methoxybenzaldehyde (XXIV) with methanesulfonyl chloride and triethylamine gives the corresponding mesylate (XXV), which is nitrated with fuming HNO3 to 2-(methanesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVI). The condensation of (XXVI) or 2-(benzenesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVIII) with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF yields 3-(2-hydroxy-3-methoxy-6-nitrophenyl)acrylic acid methyl ester (XXVII), which is benzylated with benzyl bromide and K2CO3 to the benzyl derivative (XXIX). The cyclization of (XXIX) with refluxing triethyl phosphite affords 4-benzyloxy-5-methoxy-1H-indole-2-carboxylic acid methyl ester (XXX), which is reduced to the corresponding carbaldehyde (XXXI) according to Tetrahedron Lett 1994, 50: 7657. The methylation of (XXXI) with NaH and methyl iodide in DMF yields the N-methyl derivative (XXXII), which is condensed with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF to afford 3-(4-benzyloxy-5-methoxy-1-methylindol-2-yl)acrylic acid methyl ester (XXXIII). The formylation of (XXXIII) with POCl3 and DMF gives the 4-formyl derivative (XXXIV), which is debenzylated with trimethylsilyl iodide in acetonitrile to the 4-hydroxy compound (XXXV). The oxidation of (XXXV) with Fremy's salt as before yields 3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-2-yl) acrylic acid methyl ester (XXXVI), which is treated successively with Na2S2O4, DIBAL, and finally with FeCl3, as before, to afford the dihydroxy quinone (XXII), already obtained.

参考文献 中间体
合成目标
【1】 Cotterill, A.S.; Moody, C.J.; Roffey, J.R.; An improved synthesis of the indolequinone anticancer agent EO9. Tetrahedron 1995, 51, 26, 7223-30.
【2】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
27698 methyl 2-(diethoxyphosphoryl)acetate 1067-74-9 C7H15O5P 详情 详情
(XXII) 12618 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione C14H15NO5 详情 详情
(XXIII) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(XXIV) 12620 o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde 148-53-8 C8H8O3 详情 详情
(XXV) 12621 2-formyl-6-methoxyphenyl methanesulfonate C9H10O5S 详情 详情
(XXVI) 12622 2-formyl-6-methoxy-3-nitrophenyl methanesulfonate C9H9NO7S 详情 详情
(XXVII) 12623 methyl (E)-3-(2-hydroxy-3-methoxy-6-nitrophenyl)-2-propenoate C11H11NO6 详情 详情
(XXVIII) 12624 2-formyl-6-methoxy-3-nitrophenyl benzenesulfonate C14H11NO7S 详情 详情
(XXIX) 12625 methyl (E)-3-[2-(benzyloxy)-3-methoxy-6-nitrophenyl]-2-propenoate C18H17NO6 详情 详情
(XXX) 12626 methyl 4-(benzyloxy)-5-methoxy-1H-indole-2-carboxylate C18H17NO4 详情 详情
(XXXI) 12627 4-(Benzyloxy)-5-methoxy-1H-indole-2-carbaldehyde C17H15NO3 详情 详情
(XXXII) 12628 4-(Benzyloxy)-5-methoxy-1-methyl-1H-indole-2-carbaldehyde C18H17NO3 详情 详情
(XXXIII) 12629 ethyl (E)-3-[4-(benzyloxy)-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate C22H23NO4 详情 详情
(XXXIV) 12630 ethyl (E)-3-[4-(benzyloxy)-3-formyl-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate C23H23NO5 详情 详情
(XXXV) 12631 ethyl (E)-3-(3-formyl-4-hydroxy-5-methoxy-1-methyl-1H-indol-2-yl)-2-propenoate C16H17NO5 详情 详情
(XXXVI) 12632 ethyl (E)-3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indol-2-yl)-2-propenoate C16H15NO6 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XXIII)

3) The cyclization of benzoquinone (XXXVII) with 3-amino-4-methoxycrotonic acid methyl ester (XXXVIII) gives 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylic acid methyl ester (XXXIX), which is methylated to 5-methoxy-2-(methoxymethyl)-1-methylindole-3-carboxylic acid methyl ester (XL). The oxidation of (XL) with DDQ yields the corresponding aldehyde (XLI), which is submitted to a Horner-Emmonds condensation with 2-(dimethoxyphosphoryl)acetic acid ethyl ester (XLII) in a basic medium to afford the corresponding acrylic ester (XLIII). The nitration of (XLIII) gives 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4-nitroindol-2-yl]acrylic acid ethyl ester (XLIV), the monoethyl ester analogue of compound (XVIII).The reduction of (XLIV) with Sn and 3N HCl in ethanol/water yields the corresponding 4-amino derivative (XLV), which is oxidized with Fremy's salt (nitrodisulfonic acid potassium salt) to afford 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4,7-dioxo-4,7-dihydro-1H-indo l -2-yl]acrylic acid ethyl ester (XLVI). The reduction of (XLVI) with Na2S2O4 in CHCl3/ethanol/water gives the corresponding hydroquinone (XLVII), which is first reduced with DIBAL (diisobutylaluminum hydride) in toluene/dichloromethane and then oxidized again with FeCl3 to afford 3-(hydroxymethyl)-2-(3-hydroxy-1-propenyl)-5-methoxy-1-methyl-4,7-dihydro-1H-indole-4,7-dione (XXII). Finally, this compound is treated with aziridine (XXIII) in hot methanol.

参考文献 中间体
合成目标
【1】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143.
【2】 Kinugawa, M.; Arai, H.; Nishikawa, H.; Masuda, Y.; Ogasa, T.; Tomioka, S.; Kasai, M.; Synthetic studies of the indoloquinone antitumor agent EO9. 13th Int Symp Med Chem (Sept 19-23, Paris) 1994, Abst P250.
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) 12618 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione C14H15NO5 详情 详情
(XXIII) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(XXXVII) 12633 Quinone; Benzo-1,4-quinone; 2,5-Cyclohexadiene-1,4-dione 106-51-4 C6H4O2 详情 详情
(XXXVIII) 12634 methyl (E)-3-amino-4-methoxy-2-butenoate C6H11NO3 详情 详情
(XXXIX) 12635 methyl 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylate C12H13NO4 详情 详情
(XL) 12636 methyl 5-methoxy-2-(methoxymethyl)-1-methyl-1H-indole-3-carboxylate C14H17NO4 详情 详情
(XLI) 12637 methyl 2-formyl-5-methoxy-1-methyl-1H-indole-3-carboxylate C13H13NO4 详情 详情
(XLII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(XLIII) 12639 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-1H-indole-3-carboxylate C17H19NO5 详情 详情
(XLIV) 12640 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4-nitro-1H-indole-3-carboxylate C17H18N2O7 详情 详情
(XLV) 63466 2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C26H31N3O6S2 详情 详情
(XLVI) 63467 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-3-carboxylate C17H17NO7 详情 详情
(XLVII) 63468 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-4,7-dihydroxy-5-methoxy-1-methyl-1H-indole-3-carboxylate C17H19NO7 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IX)

Ethyl 5-hydroxy-2-methylindole (I) was dimethylated with iodomethane in the presence of KH to give (II). Nitration of (II) in AcOH afforded the 4-nitroindole (III) together with some 6-nitro isomer (IV), which were separated by column chromatography. Reduction of (III) with Sn and HCl yielded the 4-aminoindole (V). This was then oxidized with Fremy's salt to afford the corresponding indolequinone (VI) (1). Quinone (VI) was reduced to the hydroquinone (VII) with sodium dithionite, and this was further reduced with DIBAL-H to give, after oxidative work-up with FeCl3 to regenerate the quinone, the 3-(hydroxymethyl) indolequinone (VIII). Finally, substitution of the methoxy group of (VIII) with aziridine (IX) in DMF yielded the target compound (2).

参考文献 中间体
合成目标
【1】 Beall, H.D.; Winski, S.; Swann, E.; Hudnott, A.R.; Cotterill, A.S.; O'Sullivan, N.; Green, S.J.; Bien, R.; Siegel, D.; Ross, D.; Moody, C.J.; Indolequinone antitumor agents: Correlation between quinone structure, rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase, and in vitro cytotoxicity. J Med Chem 1998, 41, 24, 4755.
【2】 Naylor, M.A.; et al.; Indolequinone antitumor agents: Reductive activation and elimination from (5-methoxy-1-methyl-4,7-dioxoindol-3-yl)methyl derivatives and hypoxia-selective cytotoxicity in vitro. J Med Chem 1998, 41, 15, 2720.
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) 26100 3-Carbethoxy-5-hydroxy-2-methylindole; 5-Hydroxy-2-methylindole-3-carboxylic acid ethyl ester; 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester 7598-91-6 C12H13NO3 详情 详情
(II) 26101 ethyl 5-methoxy-1,2-dimethyl-1H-indole-3-carboxylate C14H17NO3 详情 详情
(III) 26102 ethyl 5-methoxy-1,2-dimethyl-4-nitro-1H-indole-3-carboxylate C14H16N2O5 详情 详情
(IV) 26103 ethyl 5-methoxy-1,2-dimethyl-6-nitro-1H-indole-3-carboxylate C14H16N2O5 详情 详情
(V) 26104 ethyl 4-amino-5-methoxy-1,2-dimethyl-1H-indole-3-carboxylate C14H18N2O3 详情 详情
(VI) 26105 ethyl 5-methoxy-1,2-dimethyl-4,7-dioxo-4,7-dihydro-1H-indole-3-carboxylate C14H15NO5 详情 详情
(VII) 26106 ethyl 4,7-dihydroxy-5-methoxy-1,2-dimethyl-1H-indole-3-carboxylate C14H17NO5 详情 详情
(VIII) 26107 3-(hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione C12H13NO4 详情 详情
(IX) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XIV)

Acylation of aziridine (XIV) with methanesulfonyl chloride produced sulfonamide (XV). This was then condensed with piperidine (XIII) to yield the target sulfonylaminoethyl piperidine.

参考文献 中间体
合成目标
【1】 Kowalczyk, B.A.; et al.; Process development of the synthetic route to sulamserod hydrochloride. Org Process Res Dev 2001, 5, 2, 116.
【2】 Clark, R.D.; Eglen, R.; Jahangir, A.; Miller, A.B.; Gardner, J.O. (Syntex (USA), Inc.); Novel 1-phenylalkanone 5-HT4 receptor ligands. EP 0700383; JP 1996510743; WO 9427965 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 35641 1-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(4-piperidinyl)-1-propanone C16H21ClN2O3 详情 详情
(XIV) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(XV) 35642 1-(methylsulfonyl)aziridine C3H7NO2S 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

2-(Hydroxymethyl)-5-methyl-1,4-benzoquinone (III) was obtained by hydroxymethylation of toluhydroquinone (I) with formaldehyde, followed by oxidation of the resulting hydroquinone (II) with Ag2O. Then, addition of aziridine (IV) to quinone (III) furnished the title compound.

参考文献 中间体
合成目标
【1】 Remers, W.A.; Witty, T.R.; Synthesis and antitumor and antibacterial activity of benzoquinones related to the mitomycins. J Med Chem 1973, 16, 11, 1280.
【2】 Winski, S.L.; Hargreaves, R.H.J.; Butler, J.; Ross, D.; A new screening system for NAD(P)H: quinone oxidoreductase (NQO1)-directed antitumor quinones: Identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. Clin Cancer Res 1998, 4, 12, 3083.
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) 45525 2-methyl-1,4-benzenediol 95-71-6 C7H8O2 详情 详情
(II) 45526 2-(hydroxymethyl)-5-methyl-1,4-benzenediol C8H10O3 详情 详情
(III) 45527 2-(hydroxymethyl)-5-methylbenzo-1,4-quinone C8H8O3 详情 详情
(IV) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

The reaction of aziridine (I) with hydrazine gives aminoethylhydrazine (II) (1), which is then cyclized with ethyl 2,3-diphenylpropionimidate hydrochloride (III) in ethanol. (1,2)

参考文献 中间体
合成目标
【1】 Trepanier, D.L. (Dow Chem. Co.); US 3471486 .
【2】 Trepanier, D.L.; et al.; Vitrase approved by FDA as spreading agent; phase III results in vitreous hemorrhage also presented. J Med Chem 1969, 12, 2, 257.
【3】 Castaner, J.; Hillier, K.; DL - 262. Drugs Fut 1979, 4, 3, 196.
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) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(II) 41188 2-hydrazinoethylamine; 2-hydrazino-1-ethanamine C2H9N3 详情 详情
(III) 61383 ethyl 2,3-diphenylpropanimidoate hydrochloride C17H20ClNO 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XI)

Protection of 1,5,6,7-tetrahydroindol-4-one (I) with Boc2O by means of t-BuOK in refluxing THF gives the corresponding N-Boc-indolone (II), which is then reduced with H2 over Pt/C in MeOH to yield (3aR*, 4S*,7aR*)-cis-N-Boc-4-hydroxyoctahydroindole (III). Swern oxidation of alcohol (III) using (COCl)2, DMSO and Et3N in THF affords the racemic perhydroindolone (IV), which is resolved using chiral chromatography to the (3aR,7aR)-enantiomer (V). Alternatively, enantioselective acetylation of racemic alcohol (III) with vinyl acetate in the presence of immobilized Candida antarctica lipase (Novozyme 435), followed by flash chromatographic separation of the undesired (3aS,4R,7aS)-acetate provides unreacted (3aR,4S,7aR)-alcohol (VI), which is then oxidized to ketone (V) under Swern conditions. Treatment of 1-ethynyl-3-methylbenzene (VII) with BuLi in THF at –20 °C and subsequent enantioselective condensation with ketone (V) leads to propargylic alcohol (VIII), which is then N-deprotected with HCl in EtOAc to produce the amine (IX). Finally, amine (IX) is acylated with methyl chloroformate (X) in the presence of Et3N in CH2Cl2 .
Alternatively, Michael addition of aziridine (XI) to 2-cyclohexenone (XII) in toluene gives 3-(1-aziridinyl)cyclohexanone (XIII), which is submitted to aziridine ring opening by treatment with methyl chloroformate in toluene to provide methyl N-2-chloroethyl-N-(3-oxocyclohexyl)carba-mate (XIV). Intramolecular cyclization of carbamate (XIV) in the presence of pyrrolidine and Et3N in CH2Cl2 affords racemic methyl 4-oxooctahydroindole-1-carboxylate (XV), which is then subjected to chiral chromatographic separation, resulting in the (3aR,7aR)-enantiomer (XVI). Finally, 1-ethynyl-3-methylbenzene (VII) is stereospecifically added to ketone (XVI) in the presence of n-Hex-Li in THF .

参考文献 中间体
合成目标
【1】 Auberson, Y., Ofner, S., Gasparini, F. (Novartis AG; Novartis Pharma GmbH). Acetylene derivatives having mGluR5 antagonistic activity. EP 1453512, JP 2005514381, JP 200830326, US 200506591, US 7348353, US 2008146647, US 2008303226, WO 2003047581.
【2】 Kuesters, E., Acemoglu, M., Lustenberger, P., Sedelmeier, G., Schmidt, B.,Penn, G. (Novartis AG). Processes for the preparation of 4-oxo-octahydroindole-1-carbocylic acid methyl ester and derivatives thereof. CN 102119151, EP 2315748, JP 2011530566, KR 2011042222, US 2011144352, US 8084487, WO 2010018154.
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) 68376 6,7-dihydro-1H-indol-4(5H)-one;1,5,6,7-tetrahydro-4h-indol-4-one;4-0xo-4,5,6,7-tetrahydroindole;4-Oxo-1,5,6,7-tetrahydroindole 13754-86-4 C8H9NO 详情 详情
(II) 68377 tert-butyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylate 　 C13H17NO3 详情 详情
(III) 68378 racemic N-Boc-4-hydroxyoctahydroindole;racemic tert-butyl 4-hydroxyoctahydro-1H-indole-1-carboxylate 　 C13H23NO3 详情 详情
(IV) 68379 racemic tert-butyl 4-oxooctahydro-1H-indole-1-carboxylate 　 C13H21NO3 详情 详情
(V) 68380 (3aR,7aR)-tert-butyl 4-oxooctahydro- 1H-indole-1-carboxylate 　 C13H21NO3 详情 详情
(VI) 68381 (3aR,4S,7aR)-cis-N-Boc-4- hydroxyoctahydroindole;(3aR,4S,7aR)-tert-butyl 4- hydroxyoctahydro-1H-indole-1-carboxylate 　 C13H23NO3 详情 详情
(VII) 68382 1-ethynyl-3-methylbenzene;3-Ethynyltoluene;3-Methylphenylacetylene;3'-Methylphenylacetylene 766-82-5 C9H8 详情 详情
(VIII) 68384 (3aR,4S,7aR)-tert-butyl 4-hydroxy-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate 　 C22H29NO3 详情 详情
(IX) 68383 (3aR,4S,7aR)-4-(m-tolylethynyl)octahydro-1H-indol-4-ol hydrochloride 　 C17H21NO.HCl 详情 详情
(X) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(XI) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(XII) 26253 2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone 930-68-7 C6H8O 详情 详情
(XIII) 68385 3-(1-aziridinyl)cyclohexanone;3-(aziridin-1-yl)cyclohexanone 　 C8H13NO 详情 详情
(XIV) 68386 methyl N-2-chloroethyl-N-(3-oxocyclohexyl) carbamate;methyl (2-chloroethyl)(3-oxocyclohexyl)carbamate 　 C10H16ClNO3 详情 详情
(XV) 68387 racemic methyl 4-oxooctahydroindole-1-carboxylate 　 C10H15NO3 详情 详情
(XVI) 68388 (3aR,7aR)-methyl 4-oxooctahydro-1H-indole-1-carboxylate 　 C10H15NO3 详情 详情
Extended Information