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【结 构 式】 
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【分子编号】13225 【品名】N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 【CA登记号】143238-38-4 |
【 分 子 式 】C9H18N2O2 【 分 子 量 】186.2542 【元素组成】C 58.04% H 9.74% N 15.04% O 17.18% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of 2-amino-7-hydroxy-1,8-naphthyridine (I) with 5,6-dihydro-1,7-dithiin-2,3-dicarboxylic acid anhydride (II) in biphenyl-diphenyl ether at 230 C gives 5,7-dioxo-8-(7-hydroxy-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (III), which by reaction with POCl3 at 100 C is converted to the corresponding 7-chloro derivative (IV). Partial reduction of (IV) with KBH4 in methanol yields 6-(7-chloro-1,8-naphthyridin 2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (V), which is condensed with 4-chlorocarbonyl-1-(tert-butoxycarbonyl)piperazin (VI) by means of NaH in DMF affording 5-[(4-tert-butoxycarbonylpiperazin-1-yl)carbonyloxy]-6-(7-chloro-1,8-naphthyndin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (VII) Deprotection of (VII) by means of trifluoroacetic acid gives 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-[(piperazin-1-yl)carbonyloxy]-2,3,6,7-tetrahydro-5H-1,4-dithino[2,3-c]pyrrole (VIII), which is finally acetylated with propionic acid (IX) by means of dicyclohexylcarbodiimide in methylene chloride. The piperazine derivative (VI) is prepared as follows: The condensation of piperazine (X) with tert-butyl azidoformate (XI) in aqueous HCl gives 1-(tert-butoxycarbonyl)piperazine (XII), which is then condensed with phosgene in anhydrous toluene.
| 【1】 Cotrel, C.; Crisan, C.; Jeanmart, C.; Messer, M.N. (Aventis Pharma SA); Heterocyclic compounds. BE 0835325; DE 2550111; FR 2313060; FR 2322600; FR 2322601; FR 2322602; GB 1468497; JP 7670776; JP 7733685; JP 7998790; JP 8040671; JP 8051087; US 4220646 . |
| 【2】 Serradell, M.N.; Castaner, J.; Suproclone. Drugs Fut 1985, 10, 1, 45. |
| 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) | 28994 | 7-amino[1,8]naphthyridin-2-ol | C8H7N3O | 详情 | 详情 | |
| (II) | 28995 | 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C6H5NO2S2 | 详情 | 详情 | |
| (III) | 28996 | 6-(7-hydroxy[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H9N3O3S2 | 详情 | 详情 | |
| (IV) | 28997 | 6-(7-chloro[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H8ClN3O2S2 | 详情 | 详情 | |
| (V) | 28998 | 6-(7-chloro[1,8]naphthyridin-2-yl)-7-hydroxy-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-one | C14H10ClN3O2S2 | 详情 | 详情 | |
| (VI) | 28999 | tert-butyl 4-(chlorocarbonyl)-1-piperazinecarboxylate | C10H17ClN2O3 | 详情 | 详情 | |
| (VII) | 29000 | 1-(tert-butyl) 4-[6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl] 1,4-piperazinedicarboxylate | C24H26ClN5O5S2 | 详情 | 详情 | |
| (VIII) | 29001 | 6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl 1-piperazinecarboxylate | C19H18ClN5O3S2 | 详情 | 详情 | |
| (IX) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (X) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (XI) | 29002 | 2-[(azidocarbonyl)oxy]-2-methylpropane | C5H9N3O2 | 详情 | 详情 | |
| (XII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Iganidipine can be obtained by two similar ways: 1) The condensation of 1-(tert-butoxycarbonyl)piperazine (I) with isobutyraldehyde (II) and formaldehyde in acetic acid gives 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2,2-dimethylpropionaldehyde (III), which is reduced with NaBH4 in isopropanol to the corresponding alcohol (IV). The condensation of (IV) with diketene (V) by mens of dimethylaminopyridine (DMAP) in dichloromethane affords the acetoacetic ester (VI), which is cyclized with 3-nitrobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol to give the protected dihydropyridine (IX). The elimination of the tert-butoxycarbonyl group of (IX) with HCl in ethanol yields dihydropyridine (X), which is finally alkylated with allyl chloride (XI) and triethylamine in hot THF. 2) The condensation of 3-(4-allylpiperazin-1-yl)-2,2-dimethylpropanol (XII) with diketene (V) in dichloromethane gives the corresponding acetoacetic ester (XIII), which is treated with dry NH3 in methanol to yield the 3-aminocrotonic ester (XIV). Finally, this compound is cyclized with 2-(3-nitrobenzylidene)acetoacetic acid methyl ester (XV) in hot isopropanol.
| 【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Iganidipine Hydrochloride. Drugs Fut 1997, 22, 1, 23. |
| 【2】 Matsui, H.; Fukata, F.M.; Mori, T.; Kakeya, N.; Kitao, K. (Kyoto Pharmaceutical Industries, Ltd.); 1,4-Dihydropyridine derivs. and pharmaceutical compsn. Thereof. AU 8812519; EP 0289746; JP 1988225355; US 4937242 . |
| 【3】 Kakeya, N.; Fukada, F.; Nishizawa, S. (Kyoto Pharmaceutical Industries, Ltd.); 3-Aminocrotonic acid ester. JP 1991099064 . |
| 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) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (III) | 13227 | tert-butyl 4-(2,2-dimethyl-3-oxopropyl)-1-piperazinecarboxylate | C14H26N2O3 | 详情 | 详情 | |
| (IV) | 13228 | tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-1-piperazinecarboxylate | C14H28N2O3 | 详情 | 详情 | |
| (V) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VI) | 13230 | tert-butyl 4-[3-(acetoacetoxy)-2,2-dimethylpropyl]-1-piperazinecarboxylate | C18H32N2O5 | 详情 | 详情 | |
| (VII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (VIII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (IX) | 13233 | 3-[3-[4-(tert-butoxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C30H42N4O8 | 详情 | 详情 | |
| (X) | 13234 | 3-[2,2-dimethyl-3-(1-piperazinyl)propyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C25H34N4O6 | 详情 | 详情 | |
| (XI) | 13235 | Allyl chloride; 3-Chloro-1-propene | 107-05-1 | C3H5Cl | 详情 | 详情 |
| (XII) | 13236 | 3-(4-Allyl-1-piperazinyl)-2,2-dimethyl-1-propanol | C12H24N2O | 详情 | 详情 | |
| (XIII) | 13237 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl 3-oxobutanoate | C16H28N2O3 | 详情 | 详情 | |
| (XIV) | 13238 | 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl (E)-3-amino-2-butenoate | C16H29N3O2 | 详情 | 详情 | |
| (XV) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A synthesis of [3H]-KW-2189 has been published: The condensation of duocarmycin B2 (I) with tert-butoxycarbonylpiperazine (II) and 4-nitrophenyl chloroformate by means of triethylamine in dichloromethane gives the expected piperazinecarboxylate (III), which is reduced with NaBH4 in allyl alcohol to yield the hydroxy-derivative (IV). The treatment of (IV) with camphorsulfonic acid (CSA) in hot toluene affords the isomerized compound (V) along with simultaneous deprotection of the piperazine ring. Finally, compound (V) is methylated with tritiated methyl iodide and NaHCO3 in acetone/methanol.
| 【1】 Ogasa, T.; Saito, H.; Kinugawa, M.; Nagamura, S.; The synthesis of [H-3]KW-2189, a novel active antitumor antibiotic. J Label Compd Radiopharm 1997, 39, 6, 471. |
| 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) | 17752 | methyl (2S,8S)-8-(bromomethyl)-4-hydroxy-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate | C26H26BrN3O8 | 详情 | 详情 | |
| (II) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (III) | 17754 | 1-[(2S,8S)-8-(bromomethyl)-2-(methoxycarbonyl)-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indol-4-yl] 4-(tert-butyl) 1,4-piperazinedicarboxylate | C36H42BrN5O11 | 详情 | 详情 | |
| (IV) | 17755 | 1-[(1R,2S,8S)-8-(bromomethyl)-1-hydroxy-2-(methoxycarbonyl)-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indol-4-yl] 4-(tert-butyl) 1,4-piperazinedicarboxylate | C36H44BrN5O11 | 详情 | 详情 | |
| (V) | 17756 | methyl (8S)-8-(bromomethyl)-2-methyl-4-[(1-piperazinylcarbonyl)oxy]-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C31H34BrN5O8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Alkylation of N-Boc-piperazine (I) with bromoacetal (II) provided piperazine acetal (III). This was submitted to Fisher cyclization with 4-(1,2,4-triazol-4-yl)phenyl hydrazine (IV) in aqueous H2SO4 to afford the deprotected indole (V). Wittig reaction of 3-fluorobenzaldehyde (VII) with phosphorane prepared from (methoxymethyl)phosphonium salt (VI) and PhLi furnished the methoxyvinyl compound (VIII) as an E:Z mixture. Subsequent acid hydrolysis of the enol ether function of (VIII) yielded aldehyde (IX). The target compound was then obtained by reductive alkylation of piperazine (V) with aldehyde (IX) in the presence of NaBH3CN.
| 【1】 Chambers, M.S.; Goodacre, S.; Street, L.J.; et al.; 3-(Piperazinylpropyl)indoles: Selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents. J Med Chem 1999, 42, 4, 691. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 25650 | 1-fluoro-3-[(E)-2-methoxyethenyl]benzene; (E)-2-(3-fluorophenyl)ethenyl methyl ether | C9H9FO | 详情 | 详情 | |
| (VIIIb) | 53875 | (Z)-2-(3-fluorophenyl)ethenyl methyl ether; 1-fluoro-3-[(Z)-2-methoxyethenyl]benzene | n/a | C9H9FO | 详情 | 详情 |
| (I) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (II) | 25645 | 5-bromo-1-methoxypentyl methyl ether; 5-bromo-1,1-dimethoxypentane | C7H15BrO2 | 详情 | 详情 | |
| (III) | 25646 | tert-butyl 4-(5,5-dimethoxypentyl)-1-piperazinecarboxylate | C16H32N2O4 | 详情 | 详情 | |
| (IV) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 | |
| (V) | 25648 | 3-[3-(1-piperazinyl)propyl]-5-(4H-1,2,4-triazol-4-yl)-1H-indole | C17H22N6 | 详情 | 详情 | |
| (VI) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (VII) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (IX) | 25651 | 3-(3-fluorophenyl)propanal | C9H9FO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)4-Aminobenzylamine (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O. Heating of (II) with cyanamide afforded guanidine (III). The Boc protecting group of (III) was then removed by means of trifluoroacetic acid to furnish 4-guanidinobenzylamine (IV). 4-Boc-piperazine-1-carbonyl chloride (VI) (obtained by treatment of N-Boc piperazine (V) with triphosgene) was condensed with amine (IV), yielding urea (VII). The N-Boc group of (VII) was then deprotected with trifluoroacetic acid to give (VIII) (1). Dianhydromannitol (X) was converted to bischloroformate (XI) by treatment with phosgene. Then condensation of (XI) with piperazine (VIII) provided the title biscarbamate.
| 【2】 Gangloff, A.R.; Kuo, E.Y.-L.; Dener, J.M.; Rice, K.D. (Axys Pharmaceuticals, Inc.); Compsns. and methods for treating mast-cell inflammatory condition. US 6022969; WO 9609297 . |
| 【1】 Putnam, D.; Dener, J.M.; Gangloff, A.R.; Wong, M.; Rice, K.D.; Wng, V.R.; Young, W.B.; Simpson, P.J.; Kuo, E.Y.-L.; Cregar, L.; Newcomb, W.S.; Dibasic inhibitors of human mast cell tryptase. Part 2: Structure-activity relationships and requirements for potent activity. Bioorg Med Chem Lett 2000, 10, 20, 2361. |
| 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) | 35548 | 4-(aminomethyl)aniline; 4-aminobenzylamine | 4403-71-8 | C7H10N2 | 详情 | 详情 |
| (II) | 35549 | tert-butyl 4-aminobenzylcarbamate | C12H18N2O2 | 详情 | 详情 | |
| (III) | 45504 | tert-butyl 4-[[amino(imino)methyl]amino]benzylcarbamate | C13H20N4O2 | 详情 | 详情 | |
| (IV) | 45505 | N-[4-(aminomethyl)phenyl]guanidine | C8H12N4 | 详情 | 详情 | |
| (V) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VI) | 28999 | tert-butyl 4-(chlorocarbonyl)-1-piperazinecarboxylate | C10H17ClN2O3 | 详情 | 详情 | |
| (VII) | 45507 | N-(4-[[amino(imino)methyl]amino]benzyl)-1-piperazinecarboxamide | C13H20N6O | 详情 | 详情 | |
| (VIII) | 45506 | tert-butyl 4-[[(4-[[amino(imino)methyl]amino]benzyl)amino]carbonyl]-1-piperazinecarboxylate | C18H28N6O3 | 详情 | 详情 | |
| (IX) | 45508 | (3R,3aR,6R,6aR)hexahydrofuro[3,2-b]furan-3,6-diol | 3261-62-9 | C6H10O4 | 详情 | 详情 |
| (X) | 45509 | (3R,3aS,6R,6aS)-3,6-bis[(chlorocarbonyl)oxy]hexahydrofuro[3,2-b]furan | 67-73-2 | C8H8Cl2O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：1) Treatment of 6-azopenicillanate (I) with boron trifluoroetherate in a mixture of methanol and methylene chloride gives 6alpha-methoxy penicillanate (II), which on oxidation with peracetic acid gives the corresponding 1beta-oxide (III). Ring opening of the oxide (III) by heating with 2-mercaptohenzothiazole in toluene gives the intermediate (IV), which on cyclization with bromine in methylene chloride gives 2beta-bromomethyl penicillanate (V). Rearrangement of (V) with pyridine in dimethyl sulfoxide gives the cephem intermediate (VI). The sulfone derivative (VII) is obtained by oxidizing (VI) with peracetic acid in methylene chloride. Introduction of the double bound at C-2 position of the sulfone (VII) is achieved by heating with dimethylamine hydrochloride in a mixture of tert-BuOH methylene chloride and formaldehyde. Reaction of the intermediate (VIII) with diazo cyclopentane, generated in situ by treatment of cyclopentyl hydrazono with silver (I) oxide, gives 2,2,2-tricholoroethyl-7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (IX). Removal of the trichloroethyl group by treatment with Zn/glacial acetic acid gives the corresponding acid (X). Reaction of the acid (X) with oxalyl chloride followed by treatment with 4-tert-butoxycarbonyl piperidine in methylene chloride gives the intermediate (XV). Hydrolysis of the tert-butyl ester with formic acid gives the free acid (XVI). Treatment with sodium carbonate in water gives the corresponding sodium salt of Syn-1396 (XVII).
| 【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 | |
| (A) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 详情 | 详情 | |
| (I) | 27608 | 6-Diazo-2,2-dimethylpenam-3(R)-carboxylic acid 2,2,2-trichlloroethyl ester | C10H10Cl3N3O3S | 详情 | 详情 | |
| (II) | 27609 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO4S | 详情 | 详情 | |
| (III) | 27610 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO5S | 详情 | 详情 | |
| (IV) | 27611 | 2,2,2-trichloroethyl (2R)-2-[(3S)-2-(1,3-benzothiazol-2-yldisulfanyl)-3-methoxy-4-oxoazetidinyl]-3-methyl-3-butenoate | C18H17Cl3N2O4S3 | 详情 | 详情 | |
| (V) | 27612 | 2,2,2-trichloroethyl (2S,3R,6S)-3-(bromomethyl)-6-methoxy-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H13BrCl3NO4S | 详情 | 详情 | |
| (VI) | 27613 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO4S | 详情 | 详情 | |
| (VII) | 27614 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO6S | 详情 | 详情 | |
| (VIII) | 27615 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H12Cl3NO6S | 详情 | 详情 | |
| (IX) | 27616 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid 2,2,2-trichloroethyl ester S,S-dioxide | C17H20Cl3NO6S | 详情 | 详情 | |
| (X) | 27617 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide | C15H19NO6S | 详情 | 详情 | |
| (XV) | 27627 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid tert-butyl ester S,S-dioxide | C24H35N3O7S | 详情 | 详情 | |
| (XVI) | 27628 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid S,S-dioxide | C20H27N3O7S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：2) 7-ADCA (XVIII) is reacted with isobutylene and concentrated H2SO4 in DME to afford the corresponding tert-butyl ester (XIX), which on oxidation with Na2WO4 in presence of H2O2 gives the sulfone (XX). The sulfone (XX) on treatment with NaNO2 and 2.5 (N) H2SO4 in the presence of MeOH gives the 7alpha-methoxy cephem intermediate (XXI). Heating of compound (XXI) with dimethylamine hydrochloride and formaldehyde in a mixture of DMF and dioxane gives the 2-exomethylene cephem intermediate (XXII). Cycloaddition of (XXII) with diazo cyclopentane generated in situ by treatment of cyclopentyl hydrazone with silver (I) oxide, gives 7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl cephem derivative (XXIII). Deprotection of the tert-butyl ester group with formic acid gives the free acid (X). From the intermediate acid (X), the target molecule Syn-1396 and its corresponding sodium salt can be prepared, as described in Scheme 26506301a.
| 【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 | |
| (D) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 详情 | 详情 | |
| (X) | 27617 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide | C15H19NO6S | 详情 | 详情 | |
| (XV) | 27627 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid tert-butyl ester S,S-dioxide | C24H35N3O7S | 详情 | 详情 | |
| (XVI) | 27628 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid S,S-dioxide | C20H27N3O7S | 详情 | 详情 | |
| (XVIII) | 27626 | (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C8H10N2O3S | 详情 | 详情 | |
| (XIX) | 27621 | tert-butyl (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H18N2O3S | 详情 | 详情 | |
| (XX) | 27622 | tert-butyl (7R)-7-amino-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H18N2O5S | 详情 | 详情 | |
| (XXI) | 27623 | tert-butyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C13H19NO6S | 详情 | 详情 | |
| (XXII) | 27624 | tert-butyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H19NO6S | 详情 | 详情 | |
| (XXIII) | 27625 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid tert-butyl ester S,S-dioxide | C19H27NO6S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(X)2-Amino-6-bromopyridine (II) was prepared by reaction of 2,6-dibromopyridine (I) with ammonium hydroxide in a pressure bomb at 170 C. The amino group of (III) was subsequently blocked as the pyrrole derivative (IV) by condensation with 2,5-hexanedione (III). Diazotization of p-aminophenyl ethanol (V) followed by treatment with KI gave iodo derivative (VI). Subsequent reaction of (VI) with SOCl2 provided chloride (VII). Arylpyridine (VIII) was obtained by lithiation of bromopyridine (IV) with BuLi, followed by conversion to the corresponding organozinc compound with ZnCl2 and palladium-catalyzed coupling with iodide (VII). Pyrrole ring cleavage in (VIII) upon treatment with hydroxylamine furnished aminopyridine (IX). Subsequent condensation with N-Boc-piperazine (X) provided adduct (XI). After acid cleavage of the Boc group of (XI), alkylation of the resulting piperazine with phenacyl chloride (XII) yielded the title compound. Alternatively, the title compound was obtained by condensation of chloride (IX) with N-phenacylpiperazine (XIII).
| 【1】 Qian, W.; Lowe, J.A.; Volkmann, R.A.; et al.; A new class of selective and potent inhibitors of neuronal nitric oxide synthase. Bioorg Med Chem Lett 1999, 9, 17, 2569. |
| 【2】 Lowe, J.A. III; Whittle, P.J. (Pfizer Inc.); 6-Phenylpyridyl-2-amine derivs.. EP 0891332; JP 1999510513; WO 9736871 . |
| 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) | 10159 | 2,6-Dibromopyridine | 626-05-1 | C5H3Br2N | 详情 | 详情 |
| (II) | 41341 | 2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine | 19798-81-3 | C5H5BrN2 | 详情 | 详情 |
| (III) | 24848 | acetonyl acetone;1,2-Diacetylethane;a,b-Diacetylethane;2,5-Diketohexane;Diacetonyl;Acetonylacetone;2,5-Dioxohexane;2,5-hexanedione | 110-13-4 | C6H10O2 | 详情 | 详情 |
| (IV) | 41342 | 2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine | C11H11BrN2 | 详情 | 详情 | |
| (V) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (VI) | 30973 | 2-(4-iodophenyl)-1-ethanol | C8H9IO | 详情 | 详情 | |
| (VII) | 41343 | 1-(2-chloroethyl)-4-iodobenzene | C8H8ClI | 详情 | 详情 | |
| (VIII) | 41344 | 2-[4-(2-chloroethyl)phenyl]-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine | C19H19ClN2 | 详情 | 详情 | |
| (IX) | 41345 | 6-[4-(2-chloroethyl)phenyl]-2-pyridinamine; 6-[4-(2-chloroethyl)phenyl]-2-pyridinylamine | C13H13ClN2 | 详情 | 详情 | |
| (X) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XI) | 41346 | tert-butyl 4-[4-(6-amino-2-pyridinyl)phenethyl]-1-piperazinecarboxylate | C22H30N4O2 | 详情 | 详情 | |
| (XII) | 38669 | 2-chloro-1-phenyl-1-ethanone | 532-27-4 | C8H7ClO | 详情 | 详情 |
| (XIII) | 41347 | 1-phenyl-2-(1-piperazinyl)-1-ethanone | C12H16N2O | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XI)The condensation of N-(tert-butyldimethylsilyl)-4-oxoazetidine-2(S)-carboxylic acid (I) with 1-chloro-3-iodopropane (II) by means of BuLi and triisopropylamine (TIA) in THF, followed by treatment with HCl, gives the 3(R)-(3-chloropropyl) derivative (III), which is treated with tetrabutylammonium azide and tetrabutylammonium iodide in DMF to yield the 3-azidopropyl derivative (IV). The reduction of (IV) with H2 over Pd/C in DMF affords the 3-aminopropyl compound (V), which is treated with 1-[N,N'-bis(benzyloxycarbonyl)-1H-pyrazole] (VI) in the same solvent to provide the protected 3-guanidinopropyl compound (VII). The esterification of (VII) with NaHCO3, tetrabutylammonium iodide and Bn-Br in DMF gives the benzyl ester (VIII), which is condensed with N-tert-butylpiperazine-1-carboxamide (IX) and phosgene by means of TEA in toluene to yield the protected precursor (X). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in dioxane to give the target azetidine-carboxylic acid.
| 【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 . |
| 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) | 49426 | (2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 49416 | 1-Chloro-3-iodopropane | 6940-76-7 | C3H6ClI | 详情 | 详情 |
| (III) | 49417 | (2S,3R)-3-(3-chloropropyl)-4-oxo-2-azetidinecarboxylic acid | C7H10ClNO3 | 详情 | 详情 | |
| (IV) | 49418 | (2S,3R)-3-(3-azidopropyl)-4-oxo-2-azetidinecarboxylic acid | C7H10N4O3 | 详情 | 详情 | |
| (V) | 49419 | (2S,3R)-3-(3-aminopropyl)-4-oxo-2-azetidinecarboxylic acid | C7H12N2O3 | 详情 | 详情 | |
| (VI) | 49420 | benzyl (E)-[[(benzyloxy)carbonyl]amino](1H-pyrazol-1-yl)methylidenecarbamate | C20H18N4O4 | 详情 | 详情 | |
| (VII) | 49421 | (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-4-oxo-2-azetidinecarboxylic acid | C24H26N4O7 | 详情 | 详情 | |
| (VIII) | 49422 | benzyl (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-4-oxo-2-azetidinecarboxylate | C31H32N4O7 | 详情 | 详情 | |
| (IX) | 49423 | N-(tert-butyl)-1-piperazinecarboxamide | C9H19N3O | 详情 | 详情 | |
| (X) | 49424 | benzyl (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-1-([4-[(tert-butylamino)carbonyl]-1-piperazinyl]carbonyl)-4-oxo-2-azetidinecarboxylate | C41H49N7O9 | 详情 | 详情 | |
| (XI) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (XIII) | 49425 | tert-butyl 4-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C14H27N3O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IX)Coupling of 6-phenylhexanoic acid (X) with N-Boc-piperazine (IX) to give (XI), followed by acid deprotection of the Boc group of (XI), provided (6-phenylhexanoyl)piperazine (XII). This was converted to the carbamoyl chloride (XIII) upon treatment with phosgene. The condensation of carbamoyl chloride (XIII) with azetidinone (VIII) gave rise to the urea derivative (XIV). After acid cleavage of the Boc protecting group of (XIV), the resulting piperidine (XV) was condensed with N,N'-dicarbobenzoxy-S-methylisothiourea (XVI) in the presence of HgCl2, yielding the protected guanidine (XVII). This was finally deprotected by catalytic hydrogenolysis over Pd/C.
| 【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 51123 | tert-butyl 3-([(2S,3R)-2-[(benzyloxy)carbonyl]-4-oxoazetidinyl]methyl)-1-piperidinecarboxylate | C22H30N2O5 | 详情 | 详情 | |
| (IX) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (X) | 51125 | 6-Phenylcaproic acid; 6-Phenylhexanoic acid; Benzenehexanoic acid | 5581-75-9 | C12H16O2 | 详情 | 详情 |
| (XI) | 51126 | tert-butyl 4-(6-phenylhexanoyl)-1-piperazinecarboxylate | C21H32N2O3 | 详情 | 详情 | |
| (XII) | 51127 | 6-phenyl-1-(1-piperazinyl)-1-hexanone | C16H24N2O | 详情 | 详情 | |
| (XIII) | 51128 | 4-(6-phenylhexanoyl)-1-piperazinecarbonyl chloride | C17H23ClN2O2 | 详情 | 详情 | |
| (XIV) | 51129 | tert-butyl 3-[((2S,3R)-2-[(benzyloxy)carbonyl]-4-oxo-1-[[4-(6-phenylhexanoyl)-1-piperazinyl]carbonyl]azetidinyl)methyl]-1-piperidinecarboxylate | C39H52N4O7 | 详情 | 详情 | |
| (XV) | 51130 | benzyl (2S,3R)-4-oxo-1-[[4-(6-phenylhexanoyl)-1-piperazinyl]carbonyl]-3-(3-piperidinylmethyl)-2-azetidinecarboxylate | C34H44N4O5 | 详情 | 详情 | |
| (XVI) | 32861 | benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate | C18H18N2O4S | 详情 | 详情 | |
| (XVII) | 51131 | benzyl (2S,3R)-3-[[1-([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)-3-piperidinyl]methyl]-4-oxo-1-[[4-(6-phenylhexanoyl)-1-piperazinyl]carbonyl]-2-azetidinecarboxylate | C51H58N6O9 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XV)The esterification of 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid (I) gives the methyl ester (II), which is N-protected to yield 1-Boc-4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester (III). Compound (III) which is mesylated to afford 1-Boc-4(R)-(mesyloxy)pyrrolidine-2(S)-carboxylic acid methyl ester (IV). The reaction of (IV) with sodium azide affords (V), which is reduced with H2 over Pd/C in ethanol to provide 4(S)-amino-1-Boc-pyrrolidine-2(S)-carboxylic acid methyl ester (VI). The reductocondensation of (VI) with 3-methoxybenzaldehyde (VII) by means of NaBH(OAc)3 provides the secondary amine (VIII), which is acylated with 3,3-dimethylbutyryl chloride (IX) and TEA in dichloromethane to give the amide (X). The deprotection of the pyrrolidine NH of (X) by means of TFA yields the pyrrolidine (XI), which is reductocondensed with piperonal (XII) by means of NaBH3CN to afford the N-substituted pyrrolidine (XIII). The hydrolysis of the ester group of (XIII) with LiOH in methanol/water provides the carboxylic acid (XIV), which is condensed with N-Boc-piperazine (XV) by means of TBTU and DIEA in DMF to give the protected intermediate (XVI). Finally, this compound is deprotected by means of TFA in dichloromethane to furnish the target carboxamide.
| 【1】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Rubin, L. (Curis, Inc.); Mediators of hedgehog signaling pathways, compsns. and uses related thereto. WO 0126644 . |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (IV) | 15781 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (V) | 43411 | 1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VI) | 55407 | 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VII) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VIII) | 55407 | 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (IX) | 21738 | 3,3-dimethylbutanoyl chloride | 7065-46-5 | C6H11ClO | 详情 | 详情 |
| (X) | 55409 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-1,2-pyrrolidinedicarboxylate | C25H38N2O6 | 详情 | 详情 | |
| (XI) | 55410 | methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate | C20H30N2O4 | 详情 | 详情 | |
| (XII) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (XIII) | 55411 | methyl (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate | C28H36N2O6 | 详情 | 详情 | |
| (XIV) | 55412 | (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylic acid | C27H34N2O6 | 详情 | 详情 | |
| (XV) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XVI) | 55413 | tert-butyl 4-({(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]pyrrolidinyl}carbonyl)-1-piperazinecarboxylate | C36H50N4O7 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VII)The esterification of vanillic acid (I) with benzyl bromide and K2CO3 in DMF gives the protected benzyl ester (II), which is nitrated with conc. HNO3 in acetic acid to yield 4-benzyloxy-5-methoxy-2-nitrobenzoic acid benzyl ester (III). The reduction of (III) with SnCl2 in ethyl acetate affords the corresponding 2-amino compound (IV), which is cyclized with ammonium formate in DMF at 150 C to provide the quinazolinone (V). The reaction of (V) with refluxing SOCl2 gives the chloro derivative (VI), which is condensed with 1-(tert-butoxycarbonyl)piperazine (VII) by means of DIEA in hot THF to give the 4-piperazinyl quinazoline (VIII). The reductive cleavage of the benzyl protecting group of (VIII) by means of H2 over Pd/C in ethanol yields the hydroxy compound (IX), which is condensed with 3-(tosyloxy)propyl chloride (X) by means of Cs2CO3 in DMF to afford the corresponding ether (XI). The reaction of the tosyloxy group of (XI) with piperidine (XII) in DMF provides the piperidinyl derivative (XIII), which is Boc deprotected by treatment with HCl in dioxane to give the piperazinyl precursor (XIV). Finally, this compound is condensed with 4-isopropoxyphenyl isocyanate (XV) in DMF to yield the target piperazine carboxamide.
| 【1】 Pandey, A.; et al.; Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem 2002, 45, 17, 3772. |
| 【2】 Nomoto, Y.; Scarborough, R.M.; Ichimura, M.; Fujiwara, S.; Ide, S.; Oda, S.; Pandey, A.; Tsukuda, E.; Matsuno, K.; Irie, J. (Kyowa Hakko Kogyo Co., Ltd.; Millennium Pharmaceuticals, Inc.); Quinazoline derivs. as kinase inhibitors. WO 0216351 . |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 55576 | phenylmethyl 3-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H20O4 | 详情 | 详情 | |
| (III) | 55577 | phenylmethyl 5-(methyloxy)-2-nitro-4-[(phenylmethyl)oxy]benzoate | C22H19NO6 | 详情 | 详情 | |
| (IV) | 55578 | phenylmethyl 2-amino-5-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H21NO4 | 详情 | 详情 | |
| (V) | 31530 | 7-(benzyloxy)-6-methoxy-4(3H)-quinazolinone | C16H14N2O3 | 详情 | 详情 | |
| (VI) | 51531 | 1-(4-chloro-3-nitrobenzyl)-2-methyl-1H-benzimidazole | C15H12ClN3O2 | 详情 | 详情 | |
| (VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VIII) | 55579 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C25H30N4O4 | 详情 | 详情 | |
| (IX) | 55580 | 1,1-dimethylethyl 4-[7-hydroxy-6-(methyloxy)-4-quinazolinyl]-1-piperazinecarboxylate | C18H24N4O4 | 详情 | 详情 | |
| (X) | 55581 | 3-Chloropropyl-p-toluenesulfonate | C10H13ClO3S | 详情 | 详情 | |
| (XI) | 55582 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C28H36N4O7S | 详情 | 详情 | |
| (XII) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (XIII) | 55583 | 1,1-dimethylethyl 4-(6-(methyloxy)-7-{[3-(1-piperidinyl)propyl]oxy}-4-quinazolinyl)-1-piperazinecarboxylate | C26H39N5O4 | 详情 | 详情 | |
| (XIV) | 55584 | 6-(methyloxy)-4-(1-piperazinyl)-7-{[3-(1-piperidinyl)propyl]oxy}quinazoline; methyl 4-(1-piperazinyl)-7-{[3-(1-piperidinyl)propyl]oxy}-6-quinazolinyl ether | C21H31N5O2 | 详情 | 详情 | |
| (XV) | 55585 | 1-isocyanato-4-[(1-methylethyl)oxy]benzene; 4-[(1-methylethyl)oxy]phenyl isocyanate | C10H11NO2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VII)The esterification of vanillic acid (I) with benzyl bromide and K2CO3 in DMF gives the protected benzyl ester (II), which is nitrated with conc. HNO3 in acetic acid to yield 4-benzyloxy-5-methoxy-2-nitrobenzoic acid benzyl ester (III). The reduction of (III) with SnCl2 in ethyl acetate affords the corresponding 2-amino compound (IV), which is cyclized with ammonium formate in DMF at 150 C to provide the quinazolinone (V). The reaction of (V) with refluxing SOCl2 gives the chloro derivative (VI), which is condensed with 1-(tert-butoxycarbonyl)piperazine (VII) by means of DIEA in hot THF to give the 4-piperazinyl quinazoline (VIII). The reductive cleavage of the benzyl protecting group of (VIII) by means of H2 over P/C in ethanol yields the hydroxy compound (IX), which is condensed with 3-(tosyloxy)propyl chloride (X) by means of Cs2CO3 in DMF to afford the corresponding ether (XI). The reaction of the tosyloxy group of (XI) with morpholine (XII) in DMF provides the morpholinyl derivative (XIII), which is Boc deprotected by treatment with HCl in dioxane to give the piperazinyl precursor (XIV). Finally, this compound is condensed with 4-isopropoxyphenyl isocyanate (XV) in DMF to yield the target piperazine carboxamide.
| 【1】 Nomoto, Y.; Scarborough, R.M.; Ichimura, M.; Fujiwara, S.; Ide, S.; Oda, S.; Pandey, A.; Tsukuda, E.; Matsuno, K.; Irie, J. (Kyowa Hakko Kogyo Co., Ltd.; Millennium Pharmaceuticals, Inc.); Quinazoline derivs. as kinase inhibitors. WO 0216351 . |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 55576 | phenylmethyl 3-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H20O4 | 详情 | 详情 | |
| (III) | 55577 | phenylmethyl 5-(methyloxy)-2-nitro-4-[(phenylmethyl)oxy]benzoate | C22H19NO6 | 详情 | 详情 | |
| (IV) | 55578 | phenylmethyl 2-amino-5-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H21NO4 | 详情 | 详情 | |
| (V) | 31530 | 7-(benzyloxy)-6-methoxy-4(3H)-quinazolinone | C16H14N2O3 | 详情 | 详情 | |
| (VI) | 51531 | 1-(4-chloro-3-nitrobenzyl)-2-methyl-1H-benzimidazole | C15H12ClN3O2 | 详情 | 详情 | |
| (VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VIII) | 55579 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C25H30N4O4 | 详情 | 详情 | |
| (IX) | 55580 | 1,1-dimethylethyl 4-[7-hydroxy-6-(methyloxy)-4-quinazolinyl]-1-piperazinecarboxylate | C18H24N4O4 | 详情 | 详情 | |
| (X) | 55581 | 3-Chloropropyl-p-toluenesulfonate | C10H13ClO3S | 详情 | 详情 | |
| (XI) | 55582 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C28H36N4O7S | 详情 | 详情 | |
| (XII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XIII) | 55586 | 1,1-dimethylethyl 4-(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinazolinyl)-1-piperazinecarboxylate | C25H37N5O5 | 详情 | 详情 | |
| (XIV) | 55587 | methyl 7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)-6-quinazolinyl ether; 6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)quinazoline | C20H29N5O3 | 详情 | 详情 | |
| (XV) | 55585 | 1-isocyanato-4-[(1-methylethyl)oxy]benzene; 4-[(1-methylethyl)oxy]phenyl isocyanate | C10H11NO2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(VII)Treatment of 2-chloroquinoline-3-carboxylic acid (I) with oxalyl chloride affords acid chloride (II), which is subsequently coupled with methyl 3,4-diaminobenzoate (III) to yield amide (IV). Intramolecular cyclization of amino amide (IV) with Burgess reagent in refluxing THF produces the benzimidazole (V). Then, acidic hydrolysis of both methyl ester and chloroquinoline functions of (V) gives rise to the carboxylic acid (VI). Coupling of (VI) with N-Boc-piperazine (VII) furnishes amide (VIII). The N-Boc protecting group of (VIII) is finally removed by treatment with trifluoroacetic acid in CH2Cl2.
| 【1】 Hungate, R.W.; Fraley, M.E.; Hambaugh, S.R. (Merck & Co., Inc.); Tyrosine kinase inhibitors. JP 2003512353; US 6479512; WO 0128993 . |
| 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) | 61948 | 2-chloro-3-quinolinecarboxylic acid | C10H6ClNO2 | 详情 | 详情 | |
| (II) | 61950 | 2-chloro-3-quinolinecarbonyl chloride | C10H5Cl2NO | 详情 | 详情 | |
| (III) | 34921 | 3-cyanobenzoyl chloride | 1711-11-1 | C8H4ClNO | 详情 | 详情 |
| (IV) | 61951 | methyl 3-amino-4-{[(2-chloro-3-quinolinyl)carbonyl]amino}benzoate | C18H14ClN3O3 | 详情 | 详情 | |
| (V) | 61952 | methyl 2-(2-chloro-3-quinolinyl)-1H-benzimidazole-5-carboxylate | C18H12ClN3O2 | 详情 | 详情 | |
| (VI) | 61953 | 2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-benzimidazole-5-carboxylic acid | C17H11N3O3 | 详情 | 详情 | |
| (VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VIII) | 61954 | tert-butyl 4-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-benzimidazol-5-yl]carbonyl}-1-piperazinecarboxylate | C26H27N5O4 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(III)Alkylation of 8-chloro-1,3-dimethylxanthine (I) with benzyl bromide and K2CO3 affords the 7-benzyl purine (II). This is then condensed with N-Boc-piperazine (III) in EtOH upon heating at 120 C in a sealed vessel to provide the 8-piperazinyl derivative (IV). Finally, deprotection of (IV) employing trifluoroacetic acid leads to the title compound
| 【1】 Kristiansen, M.; Lundbeck, J.M.; Christiansen, L.B.; Kanstrup, A.B.; Sams, C.K. (Novo Nordisk A/S); Heterocyclic cpds., which are inhibitors of the enzyme DPP-IV. WO 0202560 . |
| 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) | 62069 | 8-chloro-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione | 85-18-7 | C7H7ClN4O2 | 详情 | 详情 |
| (II) | 62070 | 7-benzyl-8-chloro-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione | C14H13ClN4O2 | 详情 | 详情 | |
| (III) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (IV) | 62071 | tert-butyl 4-(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-piperazinecarboxylate | C23H30N6O4 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(VII)Reaction of 2-carboxybenzaldehye (I) with dimethyl phosphite in the presence of MeONa in MeOH affords the isobenzofuranylphosphonate (II), which is condensed with 2-fluoro-5-formylbenzonitrile (III) by means of triethylamine in THF to give the benzylidene-isobenzofuranone (IV). Basic hydrolysis of the nitrile group of compound (IV) followed by treatment with hydrazine hydrate leads to the phthalazinone-carboxylic acid (V) (1-3), which can also be obtained by treatment of isobenzofuranone (IV) first with hydrazine hydrate in THF, followed by hydrolysis of the resulting phthalazinone nitrile (VI) with aqueous NaOH (2). Coupling of carboxylic acid (V) with N-Boc-piperazine (VII) by means of HBTU and DIEA in dimethylacetamide yields the Boc-protected amide (VIII), which is then deprotected to compound (IX) by treatment with HCl in EtOH or MeOH. Finally, piperazine-phthalazinone (IX) is acylated with cyclopropanecarbonyl chloride (X) in the presence of triethylamine or DIEA in CH2Cl2 (1, 2). Alternatively, condensation of piperazine (XI) with cyclopropanecarbonyl chloride (X) in AcOH solution gives N-(cyclopropylcarbonyl)piperazine (XII) (2), which is then coupled with the phthalazinone-carboxylic acid (V) by means of HBTU and DIEA in acetonitrile or dimethylacetamide (2, 3). Scheme 1.
| 【1】 Martin, N.M.B., Smith, G.C.M., Jackson, S.P. et al. (KuDOS Pharmaceuticals Ltd.; Maybridge Ltd.). Phthalazinone derivatives. CA 2517629, EP 1633724, GB 2415430, JP 2006519837, JP 2008001718, US 2005059663, US 2006149059, US 2008200469, US 7449464, WO 2004080976. |
| 【2】 Menear, K.A., Ottridge, A.P., Londesbrough, D.J. et al. (KuDOS Pharmaceuticals Ltd.). Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one. US 2008146575, WO 2008047082. |
| 【3】 Menear, K.A., Adcock, C., Boulter, R. et al. 4-[3-(4-Cyclopropanecarbonyl piperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A novel bioavailable inhibitor of poly (ADP-ribose) polymerase-1. J Med Chem 2008, 51(20): 6581-91. |
| 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) | 65828 | 3-hydroxy-2-benzofuran-1(3H)-one | C8H6O3 | 详情 | 详情 | |
| (II) | 65829 | Dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate; (3-Oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dimethyl ester | 61260-15-9 | C10H11O5P | 详情 | 详情 |
| (III) | 65830 | 3-Cyano-4-fluorobenzaldehyde; 2-Fluoro-5-formylbenzonitrile | 218301-22-5 | C8H4FNO | 详情 | 详情 |
| (IV) | 65831 | 2-Fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile | 763114-25-6 | C16H8FNO2 | 详情 | 详情 |
| (V) | 65832 | 2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid | 763114-26-7 | C16H11FN2O3 | 详情 | 详情 |
| (VI) | 65833 | C16H10FN3O | 详情 | 详情 | ||
| (VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VIII) | 65834 | C25H27FN4O4 | 详情 | 详情 | ||
| (IX) | 65835 | 1-[5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine | 763111-47-3 | C20H19FN4O2 | 详情 | 详情 |
| (X) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (XI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (XII) | 65836 | 1-(Cyclopropylcarbonyl)piperazine | 59878-57-8 | C8H14N2O | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(XVIII)Amination of 5-bromo-2,4-dichloropyrimidine (VIII) with cyclopentylamine (IX) in EtOH gives 5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine (X), which is then cyclized with crotonic acid (XI) by means of DIEA, TOTP, PdCl2(PhCN)2 in THF at 70 °C followed by treatment with Ac2O to yield the 8H-pyrido[2,3-d]pyrimidinone derivative (XII). Bromination of compound (XII) with Br2 in the presence of NaOAc in AcOH provides the 6-bromopyrido[2,3-d]pyrimidinone derivative (XIII), which is then coupled with the aminopyridine derivative (IV) in the presence of LiHMDS in toluene to afford intermediate (V). Condensation of the bromo derivative (V) with butylvinylether (XIV) in the presence of DIEA, PdCl2(dppf)2.CH2Cl2 complex in n-BuOH at 95 °C affords the 6-(1-butoxyvinyl)dihydropyrido[2,3-d]pyrimidine derivative (XV) . Finally, intermediate (XV) is treated with isethionic acid (XVI) —previously prepared by acidification of sodium isethionate (XVII) with HCl in i-PrOH in MeOH/H2O at 55 °C followed by TEA in MeOH .
The aminopyridine intermediate (IV) can be prepared by condensation of Boc-piperazine (XVIII) with 5-bromo-2-nitropyridine (XIX) in the presence of TEA in DMSO at 65-70 °C to give the nitropyridine derivative (XX), which is then reduced in the presence of H2 over Pd(OH)2/C in i-PrOH .
The key intermediate diarylamine adduct (V) can also be obtained directly by coupling aminopyridine derivative (IV) with the 2-methanesulfonylpyrido[2,3-d]pyrimidinone derivative (XXI) .
| 【1】 Toogood, P.L., Harvey, P.J., Repine, J.T. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005, 48(7): 2388-406. |
| 【2】 Barvian, M.R., Quin, J. III, Sheehan, D.J. et al. (Pfizer Inc.). 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 1470124, JP 2005519909, US 2003149001, US 6936612, WO 2003062236. |
| 【4】 Beylin, V.G., Blackburn, A.C., Erdman, D.T., Toogood, P.L. (Pfizer, Inc.).Isethionate salt of a selective CDK4 inhibitor. EP 1648889, JP 2007530425, US 2005059670, WO 2005005426. |
| 【3】 Erdman, D.T., Flamme, C.M., Nelson, J.D. (Pfizer Products, Inc.). Synthesis of 2-(pyridine-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 2069344, JP 2008094834, US 2008125588, US 7781583, WO 2008032157. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 68144 | tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate | C14H22N4O2 | 详情 | 详情 | |
| (V) | 68145 | tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate | C27H34BrN7O3 | 详情 | 详情 | |
| (VIII) | 68146 | 5-bromo-2,4-dichloropyrimidine | 36082-50-5 | C4HBrCl2N2 | 详情 | 详情 |
| (IX) | 28850 | cyclopentanamine | 1003-03-8 | C5H11N | 详情 | 详情 |
| (X) | 68147 | 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine;5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine | C9H11BrClN3 | 详情 | 详情 | |
| (XI) | 20599 | (E)-2-butenoic acid; crotonic acid | 3724-65-0 | C4H6O2 | 详情 | 详情 |
| (XII) | 68148 | 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one | C13H14ClN3O | 详情 | 详情 | |
| (XIII) | 68149 | 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one | C13H13BrClN3O | 详情 | 详情 | |
| (XIV) | 59983 | 1-butoxyethylene; butyl vinyl ether | 111-34-2 | C6H12O | 详情 | 详情 |
| (XV) | 68150 | tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate | C33H45N7O4 | 详情 | 详情 | |
| (XVI) | 13359 | 2-Hydroxy-1-ethanesulfonic acid | 107-36-8 | C2H6O4S | 详情 | 详情 |
| (XVII) | 68151 | sodium isethionate；sodium 2-sulfoethanolate | C2H5NaO4S | 详情 | 详情 | |
| (XVIII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XIX) | 68152 | 5-bromo-2-nitropyridine；2-Nitro-5-bromopyridine;3-Bromo-6-nitropyridine | 39856-50-3 | C5H3BrN2O2 | 详情 | 详情 |
| (XX) | 68153 | tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate | C14H20N4O4 | 详情 | 详情 | |
| (XXI) | 68154 | 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C14H16BrN3O3S | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(VIII)Condensation of 2-bromoiodobenzene (I) with 2,4-dimethylthiophenol (II) by means of either Pd2(dba)3 or Pd(dba)2, t-BuOK and DPEphos or Pd(dba)2, BINAP and t-BuONa in toluene yields 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene (III) , which alternatively can be prepared by reaction of either 1-iodo- or 1-bromo-2,4-dimethylbenzene (IVa or IVb) with 2-bromobenzenethiol (V) in the presence of Pd2(dba)3 and DPEphos . Then, aryl bromide (III) is condensed with piperazine (VI) in the presence of Pd(dba)2, BINAP and t-BuONa in toluene to give the free base (VII) , which is finally treated with HBr in MeOH , EtOAc or toluene .
The free base (VII) can be alternatively prepared in a one-pot procedure by reaction of 2-bromoiodobenzene (I) with 2,4-dimethylthiophenol (II) and piperazine (VI) in the presence of Pd(dba)2, BINAP and t-BuONa .
Reaction of 2-bromoiodobenzene (I) with N-Boc-piperazine (VIII) by means of Pd2(dba)3 and xantphos affords the arylpiperazine (IX) , which is then condensed with 2,4-dimethylthiophenol (II) in the presence of Pd2(dba)3, t-BuOK and DPEphos in toluene at 100 °C to give the thioether (X) . Finally, compound (X) is submitted to N-deprotection with HBr in refluxing H2O .
Alternatively, reaction of thioether (III) with N-Boc-piperazine (VIII) in the presence of Pd(dba)2 or Pd2(dba)3, BINAP , and optionally, t-BuONa in toluene , provides the N-Boc-protected arylpiperazine (X), which is then N-deprotected with HCl in refluxing MeOH to give the free base (VII) .
In a solid-phase method, binding of piperazine (VI) to the p-nitrophenyl carbonate resin (XI) in the presence of NMM in DMF results in the 4-[(1-piperazinyl)carboxymethyl]phenoxymethyl polystyrene (XII), which is then condensed with [η6-1,2-dichloro-benzene][η5-cyclopentadienyl] iron hexafluorophosphate (XIII) in the presence of K2CO3 in THF to afford the N,N’-disubstituted piperazine (XIV). Finally, the resin-bound piperazine (XIV) is condensed with 2,4-dimethylthiophenol (II) (previously treated with NaH), and subsequently subjected to photolytic decomplexation, and further acidic cleavage from the resin (TFA/CH2Cl2), leading to the free base (VII) .
| 【1】 Bang-Andersen, B., Faldt, A., Moerk, A. et al. (H. Lundbeck A/S). 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment. EP 2044043, JP 2009541216, JP 2010090165, US 2010297240, WO 2007144005. |
| 【2】 Bang-Andersen, B., Ruhland, T., Smith, G. et al. Discovery of Lu AA21004: A novel compound for the treatment of mood disorders. 237th ACS Natl Meet (March 22-2, Salt Lake City) 2009, Abst MEDI 103. |
| 【3】 Moore, N., Stensboel, T.B. (H. Lundbeck A/S). 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of pain or residual symptoms in depression relating to sleep and cognition. CA 2684571, EP 2142193, JP 201052501, US 2011009422, WO 2008113359. |
| 【4】 Nicolajsen, H.V., Lopez de Diego, H., Rock, M.H. (H. Lundbeck A/S). Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. WO 2010094285. |
| 【5】 Bang-Andersen, B., Ruhland, T., Jorgensen, M. et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (LU AA21004): A novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011 54(9): 3206-21. |
| 【6】 Smith, G.P., Pueschl, A., Moltzen, E.K., Ruhland, T., Bang-Andersen, B., Andersen, K. (H. Lundbeck A/S). Phenyl-piperazine derivatives as serotonin reuptake inhibitors. EP 1436271, EP 1749818, JP 2005505585, JP 2007031447, JP 2007051149, US 2006084662, US 2006089368, US 7138407, US 7144884, US 7148238, US 2007060574, US 7683053, US 2011009423, WO 2003029232. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 68826 | 1-iodo-2,4-dimethylbenzene;2,4-Dimethyliodobenzene;1,3-Dimethyl-4-iodobenzene;4-Iodo-m-xylene | 4214-28-2 | C8H9I | 详情 | 详情 |
| (IVb) | 68827 | 1-bromo-2,4-dimethylbenzene;2,4-Dimethylbromobenzene;4-Bromo-1,3-dimethylbenzene;4-Bromo-m-xylene | 583-70-0 | C8H9Br | 详情 | 详情 |
| (I) | 68823 | 2-bromoiodobenzene;o-Iodobromobenzene;o-Bromophenyl iodide;o-Bromoiodobenzene;2-Iodobromobenzene;2-Bromophenyliodide;2-Bromo-1-iodobenzene;1-Iodo-2-bromobenzene;1-Bromo-2-iodobenzene | 583-55-1 | C6H4BrI | 详情 | 详情 |
| (II) | 68824 | 2,4-dimethylthiophenol;2,4-Dimethylbenzenethiol | 13616-82-5 | C8H10S | 详情 | 详情 |
| (III) | 68825 | 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene;(2-bromophenyl)(2,4-dimethylphenyl)sulfane | C14H13BrS | 详情 | 详情 | |
| (V) | 52030 | 2-Bromobenzenethiol; 2-Bromothiophenol;2-bromo-benzenethio;2-Bromo thiophenol | 6320-02-1 | C6H5BrS | 详情 | 详情 |
| (VI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VII) | 68828 | 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine | C18H22N2S | 详情 | 详情 | |
| (VIII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (IX) | 68829 | tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate;1-BOC-4-(2-Bromophenyl)piperazine;4-(2-BROMO-PHENYL)-PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER | 494773-35-2 | C15H21BrN2O2 | 详情 | 详情 |
| (X) | 68830 | tert-butyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate | C23H30N2O2S | 详情 | 详情 | |
| (XII) | 68831 | 4-[(1-piperazinyl)carboxymethyl]phenoxymethyl polystyrene | 详情 | 详情 | ||
| (XIII) | 68832 | [η6-1,2-dichloro-benzene][η5-cyclopentadienyl]iron hexafluorophosphate | 详情 | 详情 |