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【结 构 式】

【分子编号】19171

【品名】1-(Chloromethyl)benzene; Benzyl chloride

【CA登记号】100-44-7

【 分 子 式 】C7H7Cl

【 分 子 量 】126.58528

【元素组成】C 66.42% H 5.57% Cl 28.01%
与该中间体有关的原料药合成路线共 19 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1

该中间体在本合成路线中的序号：(II)

The condensation of ethyl p-hydroxyphenylacetate (I) with benzyl chloride (II) by means of sodium ethoxide in refluxing ethanol gives ethyl p-(benzyloxy)phenylacetate (III), which is reduced with LiAlH4 in THF to 2-(p-benzyloxyphenyl)ethanol (IV). The etherification of (IV) with cyclopropyl bromide (A) by means of NaH in hot DMF affords 4-(cyclopropylmethoxyethyl)-1-benzyloxybenzene (V), which is debenzylated by hydrogenation with H2 and Pd/C in methanol giving rise to p-(cyclopropylmethoxyethyl)phenol (VI). The condensation of (VI) with epichlorohydrin (B) by means of NaOH in water yields 1-[p-(cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (VII), which is treated with isopropylamine (C) and finally with HCl in ether.

参考文献 中间体
合成目标
【1】 Manoury, P.M.J.; et al. (Sanofi-Synthelabo ); Phenol ethers. DE 2649605; FR 2330383; GB 1515978; JP 52085146; US 4252984 .
【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Betaxolol hydrochloride. Drugs Fut 1979, 4, 12, 867.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(A) 22277 Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane 7051-34-5 C4H7Br 详情 详情
(I) 24994 Ethyl 2-(4-hydroxyphenyl)acetate 17138-28-2 C10H12O3 详情 详情
(II) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(III) 28637 Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate C17H18O3 详情 详情
(IV) 33328 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol C15H16O2 详情 详情
(V) 33329 4-(Cyclopropylmethoxyethyl)-1-benzyloxybenzene; 1-(Benzyloxy)-4-[2-(cyclopropylmethoxy)ethyl]benzene; Benzyl 4-[2-(cyclopropylmethoxy)ethyl]phenyl ether C19H22O2 详情 详情
(VI) 33330 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol C12H16O2 详情 详情
(VII) 33331 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether C15H20O3 详情 详情
(C) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The reaction of 4-amino-5-chloro-2-methoxybenzoic acid (I) with benzyl chloride (II) and NaHCO3 in refluxing water gives the N-benzyl protected compound (III), which is condensed with cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (IV) by means of methyl chloroformate and TEA in dichloromethane to yield the benzamide (V). The deprotection of (V) with KOH in refluxing isopropanol affords compound (VI) with a free piperidinic NH group that is acylated with 3-(4-fluorophenoxy)propyl chloride (VII) by means of Na2CO3 in refluxing methylisobutylketone to provide the protected adduct (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot methanol to give the target compound. Alternatively, the piperidine derivative (VI) is treated with p-toluenesulfonic acid in refluxing toluene and then debenzylated and simultaneously reductocondensed with 3-(4-fluorophenoxy)propionaldehyde (IX) by means of H2 over Pd/C in methanol to give the target compound.

参考文献 中间体
合成目标
【1】 Gutierrez Fuentes, L.G.; Process for the preparation of benzamides. ES 2019047 .
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) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(II) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(III) 49580 4-(benzylamino)-5-chloro-2-methoxybenzoic acid C15H14ClNO3 详情 详情
(IV) 19574 (4-carboxybutyl)(triphenyl)phosphonium chloride C23H24ClO2P 详情 详情
(V) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情
(VI) 49582 4-(benzylamino)-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide C21H26ClN3O3 详情 详情
(VII) 30524 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane 1716-42-3 C9H10ClFO 详情 详情
(VIII) 49583 4-(benzylamino)-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide C30H35ClFN3O4 详情 详情
(IX) 49584 3-(4-fluorophenoxy)propanal C9H9FO2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(X)

5) The esterification of (VI) with 3-hydroxypipendine (VIII) as before gives the corresponding ester (IX), which is then benzylated with benzyl chloride (X) by means of triethylamine in refluxing THF.

参考文献 中间体
合成目标
【1】 Muto, K.; Kuroda, T.; Karasawa, A.; Yamada, K.; Nakamizo, N. (Kyowa Hakko Kogyo Co., Ltd.); 1,4-Dihydropyridine derivatives. CA 1246078; EP 0106275; ES 526441 .
【2】 Prous, J.; Castaner, J.; KW-3049. Drugs Fut 1986, 11, 11, 936.
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) 13950 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid C16H16N2O6 详情 详情
(VIII) 24255 3-piperidinol 6859-99-0 C5H11NO 详情 详情
(IX) 24256 3-methyl 5-(3-piperidinyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate C21H25N3O6 详情 详情
(X) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 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 Oxidation of 1-octyn-3-ol (I) with chromium trioxide gives the 3-oxooctyne (II), which by reaction with imidazole (III) yields (E)-1-(3-oxoocten-1-yl)imidazole (IV). Reduction of this compound with sodium borohydride gives (E)-1,3-hydroxyocten-1-yl)imidazole (V) . Finally, the latter is etherified with benzyl chloride (VI).

参考文献 中间体
合成目标
【1】 Pailer, N.; Gutwiller, H.; Mh Chem 1977, 108, Suppl. 1, 653.
【2】 Bonne, C.; Coquelet, C.; Sincholle, D. (Chauvin Laboratories SA); Therapeutic compsn. based on imidazoles, especially for the treatment of thromboses; imidazoles and process for their preparation. EP 0033432 .
【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; CBS-645. Drugs Fut 1983, 8, 10, 843.
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) 36230 1-Octyn-3-ol 818-72-4 C8H14O 详情 详情
(II) 36231 1-octyn-3-one C8H12O 详情 详情
(III) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(IV) 36232 (E)-1-(1H-imidazol-1-yl)-1-octen-3-one C11H16N2O 详情 详情
(V) 36233 (E)-1-(1H-imidazol-1-yl)-1-octen-3-ol C11H18N2O 详情 详情
(VI) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 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 5-acetylsalicylamide (I) with benzyl chloride (II) by means of sodium methoxide in hot DMF gives 4-benzyloxy-3-carbamoylacetophenone (III), which by bromination with Br2 in refluxing CHCl3 is converted into 4-benzyloxy-3-carbamoylphenacyl bromide (IV). The condensation of (IV) with N-(4-phenyl-2-butyl)benzylamine (V) (prepared from benzylamine (VI) and 4-phenyl-2-butanone (VII), p-toluenesulfonic acid and NaBH4 in benzene -methanol) by means of K2CO3 in DMF yields 2-benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide (VIII), which is reduced with NaBH4 in ethanol to afford 2-benzyloxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)-N-benzylamino]ethyl]benzamide (IX). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in ethanol. The separation into its optical isomers is performed by conventional methods.

参考文献 中间体
合成目标
【1】 Gold, E.H.; Chang, W. (Schering Corp.); A phenylalkylaminoethylsalicylamide, its preparation and pharmaceutical compositions containing it. CA 1151211; DD 150457; EP 0009702; JP 55055147; ZA 7904872 .
【2】 Gold, E.H.; Chang, W. (Schering Biotech Corp.); Diastereoisomers of 5-(1-hydroxy-2-(1-methyl-3-phenylpropylamino)ethyl)salicylamide. US 4173583 .
【3】 Serradell, M.N.; Castaner, J.; Weetman, D.F.; Blancafort, P.; Sch-19,927. Drugs Fut 1982, 7, 11, 815.
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) 32058 5-Acetyl-2-hydroxybenzamide; 5-Acetylsalicylamide 40187-51-7 C9H9NO3 详情 详情
(II) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(III) 32059 4-Benzyloxy-3-carbamoylacetophenone; 5-Acetyl-2-(benzyloxy)benzamide C16H15NO3 详情 详情
(IV) 32060 2-(Benzyloxy)-5-(2-bromoacetyl)benzamide; 4-Benzyloxy-3-carbamoylphenacyl bromide; 2-Benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide C16H14BrNO3 详情 详情
(V) 30353 N-benzyl-N-(1-methyl-3-phenylpropyl)amine; N-(4-phenyl-2-butyl)benzylamine; N-benzyl-4-phenyl-2-butanamine C17H21N 详情 详情
(VI) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(VII) 32061 4-phenyl-2-butanone 2550-26-7 C10H12O 详情 详情
(VIII) 32060 2-(Benzyloxy)-5-(2-bromoacetyl)benzamide; 4-Benzyloxy-3-carbamoylphenacyl bromide; 2-Benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide C16H14BrNO3 详情 详情
(IX) 32063 5-[2-[Benzyl(1-methyl-3-phenylpropyl)amino]-1-hydroxyethyl]-2-(benzyloxy)benzamide; 2-Benzyloxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)-N-benzylamino]ethyl]benzamide C33H36N2O3 详情 详情
(X) 32064 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide 36894-69-6 C19H24N2O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(IV)

By cyclization of 2-amino-3-benzyloxypyridine (I) with 3-chloro-4-oxopentanonitrile (II) by means of thiethylamine in ethanol. Compound (I) is prepared by benzylation of 2-amino-3-hydroxypyridine (III) with benzyl chloride (IV) by means of NaOH in water-CH2Cl2. Compound (II) is prepared by chlorination of 4-oxopentanonitrile (V) with SO2Cl2 in ether.

参考文献 中间体
合成目标
【1】 Puchalski, C.; Bristol, J.A.; EP 0033094 .
【2】 Hillier, K.; Serradell, M.N.; Castaner, J.; Blancafort, P.; SCH-28,080. Drugs Fut 1982, 7, 10, 755.
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) 37087 3-(benzyloxy)-2-pyridinylamine; 3-(benzyloxy)-2-pyridinamine 24016-03-3 C12H12N2O 详情 详情
(II) 37089 3-chloro-4-oxopentanenitrile C5H6ClNO 详情 详情
(III) 37086 2-amino-3-pyridinol; 2-Amino-3-hydroxypyridine 16867-03-1 C5H6N2O 详情 详情
(IV) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(V) 37088 4-oxopentanenitrile C5H7NO 详情 详情

合成路线7

该中间体在本合成路线中的序号：

The benzoylation of 2'-deoxy-5-iodouridine (I) with benzoyl chloride by means of pyridine in dichloromethane gives 5'-O-benzoyl-2'-deoxy-5-iodouridine (II), which is treated with benzyl trichloroacetimidate (III) and trifluoromethanesulfonic acid in dichloromethane - THF to afford the 3'-O-benzyl derivative (IV). The hydrolysis of (IV) with sodium ethoxide in ethanol yields 3'-O-benzyl-2'-deoxy-5-iodouridine (V), which is finally trifluoromethylated with bromotrifluoromethane and copper in pyridine-DMF by means of dimethylaminopyridine. The tritylation of 2'-deoxyuridine (IX) with trityl chloride in hot pyridine gives 2'-deoxy-5'-O-trityluridine (X), which is benzylated with benzyl chloride and NaH in THF yielding 3'-O-benzyl-2'-deoxy-5'-O-trityluridine (XI). The photochemical trifluoromethylation of (XI) with N-nitroso-N-(trifluoromethyl)trifluoromethanesulfonamide and biacetyl in acetonitrile irradiated with a high-pressure Hg lamp in a glass tube at room temperature affords 3'-O-benzyl-2'-deoxy-5-(trifluoromethyl-5'-O-trityluridine (XII), which is finally deprotected with HCl in methanol.

参考文献 中间体
合成目标
【1】 Fujii, S.; Yamashita, J.; Matsumoto, H.; Takeda, S.; Terada, T.; Yasumoto, M.; Unemi, N. (Taiho Pharmaceutical Co., Ltd.); Novel 2'-deoxy-5-substd. uridine derivs., processes for preparing the same and antitumor agent containing the same. EP 0129984; ES 8606381; ES 8606382; ES 8607982; ES 8706715; JP 1984216899; JP 1985061591 .
【2】 Yasumoto, M.; Matsumoto, H.; Tada, Y.; Kobayashi, K.; Noguchi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 3'-O-benzyl-2'-deoxy-beta-uridines. JP 1987187484 .
【3】 Yamashita, J.-I.; Takeda, S.; Matsumoto, H.; Unemi, N.; Yasumoto, M.; Studies on antitumor agents. 8. Antitumor activities of O-alkyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine and 2'-deoxy-5-fluorouridine. J Med Chem 1989, 32, 1, 136-139.
【4】 Hoshi, A.; Prous, J.; Castaner, J.; FTC-092. Drugs Fut 1990, 15, 8, 790.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 31154 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione 54-42-2 C9H11IN2O5 详情 详情
(II) 31155 [(2R,3S,5R)-3-hydroxy-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate C16H15IN2O6 详情 详情
(III) 31156 benzyl 2,2,2-trichloroethanimidoate 81927-55-1 C9H8Cl3NO 详情 详情
(IV) 31157 [(2R,3S,5R)-3-(benzyloxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate C23H21IN2O6 详情 详情
(V) 31158 1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione C16H17IN2O5 详情 详情
(IX) 11875 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine 951-78-0 C9H12N2O5 详情 详情
(X) 31159 1-[(2R,4S,5R)-4-hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C28H26N2O5 详情 详情
(XI) 31160 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C35H32N2O5 详情 详情
(XII) 31161 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione C36H31F3N2O5 详情 详情

合成路线8

该中间体在本合成路线中的序号：(A)

The nitration of 8-hydroxy-3,4-dihydrocarbostyril (I) with HNO3 in acetic acid-acetic anhydride gives 5-nitro-8-hydroxy-3,4-dihydrocarbostyril (II), which is reduced with SnCl2 in concentrated HCl yielding 5-amino-8-hydroxy-3,4-dihydrocarbostyril (III). The oxidation of (III) with FeCl3 in aqueous HCl affords 5,8-dioxo-3,4,5,8-tetrahydrocarbostyril (IV), which by treatment with SO2 in water is converted into 5,8-dihydroxy-3,4-dihydrocarbostyril (V). The treatment of (V) with benzyl chloride (A) and potassium carbonate in acetone gives 5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril (VII), which by reaction with epichlorohydrin (B) by means of piperidine affords 8-benzyloxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (VII). The opening of the epoxide ring of (VII) with tert-butylamine (C) in methanol yields 8-benzyloxy-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (VIII) (1,2), which is finally hydrogenated with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; 8-Hydroxycarteolol. Drugs Fut 1980, 5, 2, 78.
【2】 Uchida, M.; et al.; Synthesis of 5-(3-tert-butylamino-2-hydroxypropxy)-8-3,4-dihydrocarbostyril hydochloride and its beta-adrenergic blocking agent. Yakugaku Zasshi 1976, 96, 5, 571-577.
【3】 Nakagawa, K.; et al.; US 4072683 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(A) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 39062 8-hydroxy-3,4-dihydro-2(1H)-quinolinone 22246-18-0 C9H9NO2 详情 详情
(II) 39063 8-hydroxy-5-nitro-3,4-dihydro-2(1H)-quinolinone C9H8N2O4 详情 详情
(III) 39064 5-amino-8-hydroxy-3,4-dihydro-2(1H)-quinolinone C9H10N2O2 详情 详情
(IV) 39065 3,4,4a,8a-tetrahydro-2,5,8(1H)-quinolinetrione C9H9NO3 详情 详情
(V) 39066 5,8-dihydroxy-3,4-dihydro-2(1H)-quinolinone C9H9NO3 详情 详情
(VI) 39067 8-(benzyloxy)-5-hydroxy-3,4-dihydro-2(1H)-quinolinone C16H15NO3 详情 详情
(VII) 39068 8-(benzyloxy)-5-(2-oxiranylmethoxy)-3,4-dihydro-2(1H)-quinolinone C19H19NO4 详情 详情
(VIII) 39069 8-(benzyloxy)-5-[3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolinone C23H30N2O4 详情 详情
(C) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VIII)

This compound can be prepared by two related ways: 1) The condensation of isatin (I) with methyl 3-phenylpropionate (II) by means of lithium diisopropylamide (LDA) in THF gives methyl alpha-benzyl-3 hydroxy-2-oxo-2,3-dihydro-1H-indole-3-acetate (III), which is reduced with LiAlH4 in THF to afford beta-benzylindole-3-ethanol (IV). The cyclization of (IV) with methyl propionylacetate (V) by means of boron trifluoride ethearate to toluene yields methyl 4-benzyl-1-ethyl 1,3,4,9 tetrahydropyrano[3,4-b]indole-1-acetate (VI), which is finally hydrolyzed with NaOH in refluxing ethanol. 2) The alkylation of methyl indole-3-acetate (VII) with benzyl chloride (VIII) by means of LDA o THF gives methyl alpha-benzylindole-3-acetate (IX), which is reduced with LiAlH4 in THF to the alcohol (IV), already obtained.

参考文献 中间体
合成目标
【1】 Gavin, G.; Katz, A.H.; Conway, K.M.; Asselin, A.A.; Demerson, C.A.; Guinoso, C.; Shah, V.; Mobilio, D.; Noureldin, R.; Humber, L.G.; Chau, T.T.; Jensen, N.P.; Schimid, J.; Shaw, C.-C.; Weichman, B.M.; Van Engen, D.; Synthesis and analgesic activity of pemedolac (cis. J Med Chem 1988, 31, 6, 1244.
【2】 Katz, A.H.; Demerson, C.A.; Humber, L.G. (American Home Products Corp.); Substd. 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-ac. EP 0238226; JP 1987221688; US 4670462; US 4775690 .
【3】 Castaner, J.; Prous, J.; Pemedolac. Drugs Fut 1988, 13, 9, 834.
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) 14098 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin 91-56-5 C8H5NO2 详情 详情
(II) 23523 methyl 3-phenylpropanoate 103-25-3 C10H12O2 详情 详情
(III) 23524 methyl 2-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-3-phenylpropanoate C18H17NO4 详情 详情
(IV) 23525 2-(1H-indol-3-yl)-3-phenyl-1-propanol C17H17NO 详情 详情
(V) 15536 methyl 3-oxopentanoate 30414-53-0 C6H10O3 详情 详情
(VI) 23527 methyl 2-(4-benzyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate C23H25NO3 详情 详情
(VII) 23528 2-(1H-Indol-3-yl)acetic acid methyl ester 1912-33-0 C11H11NO2 详情 详情
(VIII) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(IX) 23529 methyl 2-(1H-indol-3-yl)-3-phenylpropanoate C18H17NO2 详情 详情

合成路线10

该中间体在本合成路线中的序号：

Title compound can be prepared as shown in Scheme: 1) 3,6-Dichloropyridazine (I) is converted to 3(2H)-pyridazinone (III) in two steps. 2) 3-N-(2-Benzo[1,4]dioxanylmethyl)amino-1-propanol (V), obtained by the reaction of (2-benzo[1,4]dioxanylmethyl)-4-toluenesulfonate (IV) with 3-amino-1-propanol, is N-benzylated to form the N-protected amino alcohol (VI), which on treatment with thionyl chloride affords the chloroalkyl derivative (VII). 3) Alkylation of 3(2H)-pyridazinone (III) with (VII) under phase-transfer catalysis conditions to the N-benzylated GYKI-12743 (VIII) and then removal of the N-benzyl group by hydrogenation gives GYKI-12743.

参考文献 中间体
合成目标
【1】 Kasztreiner, E.; Rabloczky, G.; Makk, N.; Jaszlits, L.; Matyus, P.; Cseh, G.; Pribusz, geb. Rapp, I.; Czakó, K.; Diesler, E.; Elekes, I.; Kaufer, L.; Kuhár, geb. Kürthy, M.; Kincsessy, J.; Kosáry, J.; Nagy, Gyöngyi geb. C. (Richter Gedeon Vegyeszeti); 3(2H)-Pyridazinone derivs., a process and intermediates for preparing them and medicaments containing them and/or other 3(2H)-pyridazinone derivatives. AU 8664496; EP 0220735; JP 87161768 .
【2】 Kasztreiner, E.; Matyus, P.; Rabloczky, G.; Jaszlits, L.; GYKI-12743. Drugs Fut 1989, 14, 7, 622.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
18522 3-amino-1-propanol 156-87-6 C3H9NO 详情 详情
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 11292 3,6-Dichloropyridazine 141-30-0 C4H2Cl2N2 详情 详情
(II) 20957 6-chloro-3(2H)-pyridazinone C4H3ClN2O 详情 详情
(III) 20958 3(2H)-pyridazinone C4H4N2O 详情 详情
(IV) 20959 2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylbenzenesulfonate C16H16O5S 详情 详情
(V) 20960 3-[(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol C12H17NO3 详情 详情
(VI) 20961 3-[benzyl(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol C19H23NO3 详情 详情
(VII) 20962 N-benzyl-3-chloro-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-propanamine; N-benzyl-N-(3-chloropropyl)-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amine C19H22ClNO2 详情 详情
(VIII) 20963 2-[3-[benzyl(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]propyl]-3(2H)-pyridazinone C23H25N3O3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(X)

This compound can be obtained by two related ways: The reaction of cyclopentanone (I) with ethyl cyanoacetate (II) by means of HOAc/NH4OAc gives the cyclopentylidene derivative (III), which by reaction with KCN yields 1-(cyanomethyl)cyclopentanecarbonitrile (IV). The hydrolysis of (IV) with HCl affords the dicarboxylic acid (V), which by reaction with Ac2O affords the corresponding cyclic anhydride (VI). Finally, the reaction of (VI) with O-benzyl hydroxylamine hydrochloride and NaHCO3 provides the target compound. Alternatively, the cyclic anhydride (VI) is treated with hydroxylamine hydrochloride and Na2CO3 to gives the N-hydroxyimide (VIII), which is converted into its sodium salt (IX) by means of NaOEt in EtOH, and finally alkylated with benzyl chloride (X) to provide the target compound.

参考文献 中间体
合成目标
【1】 Scott, K.R.; Nicholson, J.M.; Edafiogho, I.O.; Farrar, V.A.; Hinko, C.N.; Moore, J.A.; Imidooxy anticonvulsants: Structural analogs with special emphasis on N-(benzyloxy)-2-azaspiro[4,4]nonane-1,3-dione. Drugs Fut 1992, 17, 5, 395.
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) 15113 cyclopentanone 120-92-3 C5H8O 详情 详情
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(III) 43191 ethyl 2-cyano-2-cyclopentylideneacetate 5407-83-0 C10H13NO2 详情 详情
(IV) 43192 1-(cyanomethyl)cyclopentanecarbonitrile C8H10N2 详情 详情
(V) 43193 1-(carboxymethyl)cyclopentanecarboxylic acid C8H12O4 详情 详情
(VI) 27158 2-oxaspiro[4.4]nonane-1,3-dione C8H10O3 详情 详情
(VII) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(VIII) 43194 2-hydroxy-2-azaspiro[4.4]nonane-1,3-dione C8H11NO3 详情 详情
(IX) 43195 sodium 1,3-dioxo-2-azaspiro[4.4]nonan-2-olate C8H10NNaO3 详情 详情
(X) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情

合成路线12

该中间体在本合成路线中的序号：

The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot ethanol/water gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII). The protection of the amino group of (VII) with Boc2O and K2CO3 in methyl tert-butyl ether yields the carbamate (VIII), which is debenzylated with ammonium formate over Pd/C in methanol affording the amino compound (IX). The condensation of (IX) with 2-(2,6-dimethylphenoxy)acetic acid (X) by means of EDAC in DMF provides the corresponding amide (XI), which is deprotected at the carbamate group with TFA in dichloromethane to give (XII) with a free amino group. Finally, this compound is condensed with 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid (XIII) by means of EDAC in DMF or SOCl2 and imidazole to furnish the target compound. The intermediate 2-(2,6-dimethylphenoxy)acetic acid (X) has been obtained by condensation of 2,6-dimethylphenol (XIV) with ethyl 2-bromoacetate (XV) by means of Cs2CO3 in refluxing dioxane to give the acetate ester (XVI), which is hydrolyzed with LiOH ethanol/water to afford the target intermediate (X).

参考文献 中间体
合成目标
【1】 Stoner, E.J.; et al.; Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling. Org Process Res Dev 1999, 3, 2, 145.
【2】 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 .
【3】 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 37670 benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate C30H29NO2 详情 详情
(III) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(IV) 38263 (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile C25H24N2O 详情 详情
(V) 18327 benzyl(chloro)magnesium 6921-34-2 C7H7ClMg 详情 详情
(VI) 37671 (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one C32H32N2O 详情 详情
(VII) 37672 (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol C32H36N2O 详情 详情
(VIII) 38542 tert-butyl (1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentylcarbamate C37H44N2O3 详情 详情
(IX) 38543 tert-butyl (1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate C23H32N2O3 详情 详情
(X) 38270 2-(2,6-dimethylphenoxy)acetic acid C10H12O3 详情 详情
(XI) 38545 tert-butyl (1S,3S,4S)-1-benzyl-4-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenylpentylcarbamate C33H42N2O5 详情 详情
(XII) 38546 N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide C28H34N2O3 详情 详情
(XIII) 38264 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid C9H16N2O3 详情 详情
(XIV) 38388 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile C12H9N3O 详情 详情
(XV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XVI) 38544 ethyl 2-(2,6-dimethylphenoxy)acetate C12H16O3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

The reaction of 6-methoxybenzo[b]thiophene (I) with triisopropyl borate by means of BuLi in THF gives the boronic acid (II), which is condensed with 4-(methanesulfonyloxy)phenyl bromide (III) by means of sodium carbonate in toluene, yielding the intermediate (IV). The demethylation of (IV) with boron tribromide in dichloromethane affords phenol (V), which is protected with benzyl chloride (VI) and cesium carbonate to afford the benzyl ether (VII). The reduction of (VII) with LiAlH4 in THF provides the phenol (VIII), which is methylated with NaH and methyl iodide to the ether (IX). The bromination of (IX) with Br2 and NaHCO3 in CHCl3 affords the 3-bromo derivative (X), which is oxidized with H2O2 in TFA/dichloromethane to the sulfoxide (XI). The condensation of (XI) with 4-[2-(1-piperidinyl)ethoxy]phenol (XII) in basic medium gives the expected condensation product (XIII), which is reduced at the sulfinyl group to yield the protected compound (XIV). Finally, this compound is debenzylated by hydrogenation by means of ammonium formate over Pd/C in ethanol/ethyl acetate and converted to its hydrochloride salt by treatment with ethyl ether/HCl in ethyl acetate.

参考文献 中间体
合成目标
【1】 Palkowitz, A.D. (Eli Lilly and Company); Benzothiophene cpds., intermediates, compsns., and methods. EP 0729956; JP 1997183776; US 5488058; US 5492922; US 5510357; US 5856339 .
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) 25014 6-methoxy-1-benzothiophene; 1-benzothiophen-6-yl methyl ether C9H8OS 详情 详情
(II) 25015 6-methoxy-1-benzothiophen-2-ylboronic acid C9H9BO3S 详情 详情
(III) 25016 4-bromophenyl methanesulfonate C7H7BrO3S 详情 详情
(IV) 25017 4-(6-methoxy-1-benzothiophen-2-yl)phenyl methanesulfonate C16H14O4S2 详情 详情
(V) 25018 4-(6-hydroxy-1-benzothiophen-2-yl)phenyl methanesulfonate C15H12O4S2 详情 详情
(VI) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(VII) 25020 4-[6-(benzyloxy)-1-benzothiophen-2-yl]phenyl methanesulfonate C22H18O4S2 详情 详情
(VIII) 25021 4-[6-(benzyloxy)-1-benzothiophen-2-yl]phenol C21H16O2S 详情 详情
(IX) 25022 6-(benzyloxy)-2-(4-methoxyphenyl)-1-benzothiophene; benzyl 2-(4-methoxyphenyl)-1-benzothiophen-6-yl ether C22H18O2S 详情 详情
(X) 25023 6-(benzyloxy)-3-bromo-2-(4-methoxyphenyl)-1-benzothiophene; benzyl 3-bromo-2-(4-methoxyphenyl)-1-benzothiophen-6-yl ether C22H17BrO2S 详情 详情
(XI) 25024 6-(benzyloxy)-3-bromo-2-(4-methoxyphenyl)-1H-1-benzothiophen-1-one C22H17BrO3S 详情 详情
(XII) 25025 4-[2-(1-piperidinyl)ethoxy]phenol C13H19NO2 详情 详情
(XIII) 25026 6-(benzyloxy)-2-(4-methoxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-1H-1-benzothiophen-1-one C35H35NO5S 详情 详情
(XIV) 25027 benzyl 2-(4-methoxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-1-benzothiophen-6-yl ether; 1-[2-(4-[[6-(benzyloxy)-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperidine C35H35NO4S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(V)

The reaction of m-xylenediamine (I) with triethylamine and di-tert-butyldicarbonate (II) gives the corresponding tert-butyl N-[3-(aminomethyl)benzyl] carbamate hydrochloride (III), which is converted into the tert-butyl N-[3-((acetimidoyl)aminomethyl]benzyl) carbamate hydrochloride (VII) by reaction with S-benzylthioacetimidate hydrochloride (VI). This intermediate (VI) could be obtained by reaction of thioacetamide (IV) with benzyl chloride (V). Finally, compound (VII) is deprotected with HCl to afford the corresponding N-[3-(aminomethyl)benzyl] acetamidine hydrochloride.

参考文献 中间体
合成目标
【1】 Itabashi, K.; Takido, T.; An efficient synthesis of unsymmetrical sulfides using liquid-liquid phase transfer catalysis. Synthesis 1987, 817.
【2】 Oplinger, J.A.; Garvey, E.P.; Furfine, E.S.; Shearer, B.G.; Collins, J.L. (Glaxo Wellcome plc); Acetamidine derivs. and their use as inhibitors for the nitric oxide synthase. EP 0799191; JP 1999500711; US 5866612; WO 9619440 .
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) 19167 3-(aminomethyl)benzylamine; [3-(aminomethyl)phenyl]methanamine 1477-55-0 C8H12N2 详情 详情
(II) 13214 Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate 24424-99-5 C10H18O5 详情 详情
(III) 19169 tert-butyl N-[3-(aminomethyl)benzyl]carbamate; tert-butyl 3-(aminomethyl)benzylcarbamate 108467-99-8 C13H20N2O2 详情 详情
(IV) 19170 ethanethioamide 62-55-5 C2H5NS 详情 详情
(V) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(VI) 19172 benzyl ethanimidothioate C9H11NS 详情 详情
(VII) 19173 tert-butyl 3-[(ethanimidoylamino)methyl]benzylcarbamate C15H23N3O2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

Alkylation of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (I) at the N-2 with benzyl chloride (II) in the presence of NaH in DMF yielded the 2-benzyl derivative (III), which was further alkylated with 2-chlorobenzyl chloride (IV) at the N-4 to provide the title compound.

参考文献 中间体
合成目标
【1】 Arranz, E.; Díaz, J.A.; Ingate, S.T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Vega, S.; Novel 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine derivatives as non-nucleoside reverse transcriptase inhibitors that inhibit human immunodeficiency virus type 1 replication. J Med Chem 1998, 41, 21, 4109.
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) 27304 1lambda(6)-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C5H4N2O3S2 详情 详情
(II) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(III) 27305 2-benzyl-2H-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C12H10N2O3S2 详情 详情
(IV) 10205 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride 611-19-8 C7H6Cl2 详情 详情

合成路线16

该中间体在本合成路线中的序号：

Maltol (I) was protected as the benzyl ether (II) by means of benzyl chloride, and subsequently treated with 1-(2-aminoethyl)piperidine (III) in refluxing ethanol to produce the substituted pyridone (IV). The benzyl protecting group of (IV) was finally removed with boron tribromide, yielding the title hydroxypyridone, which was isolated as the dihydrobromide salt.

参考文献 中间体
合成目标
【1】 Aytemir, M.D.; et al.; New 4(1H)-pyridinone derivatives as analgesic agents. Arzneim-Forsch Drug Res 1999, 49, 3, 250.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 13671 Hydroxymethylpyrone; 3-Hydroxy-2-methyl-4H-pyran-4-one；Maltol;3-Hydroxy-2-methyl-4-pyrone 118-71-8 C6H6O3 详情 详情
(II) 12074 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one 61049-69-2 C13H12O3 详情 详情
(III) 24646 2-(1-piperidinyl)-1-ethanamine 27578-60-5 C7H16N2 详情 详情
(IV) 31300 3-(benzyloxy)-2-methyl-1-[2-(1-piperidinyl)ethyl]-4(1H)-pyridinone C20H26N2O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：

Reaction of 3-fluoroaniline (I) with formic acid gave formanilide (II), which was reduced by means of LiAlH4 to afford 3-fluoro-N-methylaniline (III). Further alkylation of (III) with benzyl chloride provided the tertiary amine (IV). Vilsmeier-Haack formylation of (IV) with POCl3 and DMF yielded aldehyde (V), which was condensed with nitroethane in the presence of ammonium acetate to give the 2-nitropropene derivative (VI). After reduction of (VI) to the amine (VII) with LiAlH4, condensation with chloroacetyl chloride afforded chloracetamide (VIII). Subsequent displacement of the chlorine of (VIII) with dibenzylamine yielded the tertiary amine (IX). Finally, hydrogenolytic debenzylation of (IX) in the presence of Pd/C furnished the title compound.

参考文献 中间体
合成目标
【1】 Larsson, L.-G.; Florvall, L.; Ross, S.B.; Fagervall, I.; Prodrugs of neuron-selective monoamine oxidase inhibitors: Amino acid derivatives of 1-(4-aminophenyl)-2-aminopropanes. Eur J Med Chem 1999, 34, 2, 137.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
12117 Nitroethane; 1-Nitroethane 79-24-3 C2H5NO2 详情 详情
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 20697 3-fluoroaniline; 3-fluorophenylamine 372-19-0 C6H6FN 详情 详情
(II) 29575 3-fluorophenylformamide C7H6FNO 详情 详情
(III) 20700 3-fluoro-N-methylaniline; N-(3-fluorophenyl)-N-methylamine C7H8FN 详情 详情
(IV) 29576 N-benzyl-3-fluoro-N-methylaniline; N-benzyl-N-(3-fluorophenyl)-N-methylamine C14H14FN 详情 详情
(V) 29577 4-[benzyl(methyl)amino]-2-fluorobenzaldehyde C15H14FNO 详情 详情
(VI) 29578 N-benzyl-N-[3-fluoro-4-[(E)-2-nitro-1-propenyl]phenyl]-N-methylamine; N-benzyl-3-fluoro-N-methyl-4-[(E)-2-nitro-1-propenyl]aniline C17H17FN2O2 详情 详情
(VII) 29579 N-[4-(2-aminopropyl)-3-fluorophenyl]-N-benzyl-N-methylamine; 4-(2-aminopropyl)-N-benzyl-3-fluoro-N-methylaniline C17H21FN2 详情 详情
(VIII) 29580 N-(2-[4-[benzyl(methyl)amino]-2-fluorophenyl]-1-methylethyl)-2-chloroacetamide C19H22ClFN2O 详情 详情
(IX) 29581 N-(2-[4-[benzyl(methyl)amino]-2-fluorophenyl]-1-methylethyl)-2-(dibenzylamino)acetamide C33H36FN3O 详情 详情

合成路线18

该中间体在本合成路线中的序号：

Alkylation of an equimolecular mixture of trans-2,5-dimethylpiperazine dihydrochloride (I) and the free base (II) with benzyl chloride produced the racemic monobenzyl piperazine, which was resolved using (-)-tartaric acid to yield the required (2R,5S)-isomer (III). (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (IV) was protected as the silyl derivative (V) using bis(trimethylsilyl)urea, and subsequently converted to acid chloride (VI) by means of oxalyl chloride. Coupling of acid chloride (VI) with the chiral piperazine (III) afforded amide (VII), which was desilylated in methanolic HCl yielding (VIII). Hydrogenolysis of the N-benzyl group of (VIII) over Pd/C gave piperazine (IX). Finally, coupling of (IX) with 4-cyanobenzoyl chloride (X) furnished the corresponding bisamide.

参考文献 中间体
合成目标
【1】 Anderson, R.C.; Aicher, T.D.; Bebernitz, G.R.; et al.; (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamides are orally active inhibitors of pyruvate dehydrogenase kinase. J Med Chem 1999, 42, 15, 2741.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I),(II) 20687 (2R,5S)-2,5-dimethylpiperazine C6H14N2 详情 详情
(III) 34550 (2R,5S)-1-benzyl-2,5-dimethylpiperazine C13H20N2 详情 详情
(IV) 34551 (2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid 114715-77-4 C4H5F3O3 详情 详情
(V) 34552 trimethylsilyl (2R)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoate C10H21F3O3Si2 详情 详情
(VI) 34553 (2S)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoyl chloride C7H12ClF3O2Si 详情 详情
(VII) 34554 (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]-1-propanone C20H31F3N2O2Si 详情 详情
(VIII) 34555 (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone C17H23F3N2O2 详情 详情
(IX) 34556 (2R)-1-[(2S,5R)-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone C10H17F3N2O2 详情 详情
(X) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

Ethyl ester (II) is alkylated with benzyl chloride (I) by means of K2CO3 in acetone to yield 4-benzyloxy derivative (III), which is then hydrolyzed with KOH in H2O/DMSO to provide carboxylic acid (IV). Depside formation between derivative (IV) and ethyl ester (II) by means of trifluoroacetic anhydride in toluene furnishes ethyl benzoate derivative (V), which is finally hydrogenated over Pd/C in AcOEt to yield the target product.

参考文献 中间体
合成目标
【1】 Kumar, S.; Muller, K.; Depsides as non-redox inhibitors of leukotriene B4 biosynthesis and HaCaT cell growth. 1.Novel analogues of barbatic and diffractaic acid. Eur J Med Chem 1999, 34, 12, 1035.
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) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(II) 47148 ethyl 2,4-dihydroxy-3,6-dimethylbenzoate C11H14O4 详情 详情
(III) 47149 ethyl 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoate C18H20O4 详情 详情
(IV) 47150 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoic acid C16H16O4 详情 详情
(V) 47151 ethyl 4-[[4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoyl]oxy]-2-hydroxy-3,6-dimethylbenzoate C27H28O7 详情 详情
Extended Information