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【结 构 式】 
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【分子编号】12831 【品名】ethyl ethanimidoate 【CA登记号】1000-84-6 |
【 分 子 式 】C4H9NO 【 分 子 量 】87.1216 【元素组成】C 55.15% H 10.41% N 16.08% O 18.36% |
合成路线1
该中间体在本合成路线中的序号：(G)Compound can be prepared in three different related ways: 1) The reaction of 5-(o-clorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine-2-one (I) with P2S5 in pyridine at 80 C gives the corresponding thioketone (II), which by reaction with hydrazine hydrate (A) in methanol yields 2-hydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (III). Finally, this compound is cyclized with acetic anhydride acetic acid in refluxing benzene. This cyclization can also be carried out with refluxing ethyl orthoacetate (E) and H2SO4, with acetimino ethyl ether (G) in refluxing chloroform, with acetamidine hydrochloride (C) and 2-methylimidazole (D) at 160 C or thioacetamide (F) and H2SO4 at 190 C. 2) The condensation of thioketone (II) with acetohydrazide (B) in refluxing chloroform gives 2-acetylhydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (IV), which is then cyclized with acetic acid in refluxing benzene or by heating at 205 C. 3) The acetylated compound (IV) can also be obtained by acetylation of (III) with acetic anhydride and triethylamine at room temperature.
| 【1】 Nakanishi, M.; et al.; ZA 7204610 . |
| 【2】 Thorpe, P.J.; Castaner, J.; Etizolam. Drugs Fut 1979, 4, 1, 22. |
| 【3】 Nakanishi, M.; et al.; US 3904641 . |
| 【4】 Tahara, T.; et al.; Syntheses and structure-activity relationship pf 6-aryl-4H-s-triazolo[3,4-c]thieno[2,3-e](1,4)diazepines. Arzneim-Forsch Drug Res 1978, 28, 7, 1153-58. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (G) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (D) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
| (F) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (A) | 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 |
| (B) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |
| (E) | 39465 | 1-ethoxy-1,1-ethanediol | C4H10O3 | 详情 | 详情 | |
| (I) | 39461 | 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one | C15H13ClN2OS | 详情 | 详情 | |
| (II) | 39462 | 5-(2-chlorophenyl)-7-ethyl-1,3,5a,8a-tetrahydro-2H-thieno[2,3-e][1,4]diazepine-2-thione | C15H15ClN2S2 | 详情 | 详情 | |
| (III) | 39463 | 5-(2-chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno[2,3-e][1,4]diazepine | C15H15ClN4S | 详情 | 详情 | |
| (IV) | 39464 | N'-[5-(2-chlorophenyl)-7-ethyl-3H-thieno[2,3-e][1,4]diazepin-2-yl]acetohydrazide | C17H17ClN4OS | 详情 | 详情 | |
| (C) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of 4-acetoxy-3-[(1-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with benzyl-3-pyrrolidinocrotonate (II) gives the enimine ester (III), which is hydrolyzed with HCl to the corresponding ketoester (IV). The cyclization of (IV), through the diazo compound (V) by means of rhodium acetate, yields the bicyclic ketoester (VI). The condensation of (VI) with 1-(4-nitrobenzyloxycarbonyl)-3-mercaptopyrrolidine (VII) affords the protected carbapenem compound (VIII), which is deprotected by hydrogenation with H2 over Pd/C in THF giving 6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)-1-carbapen-2-em-2-carboxylic acid (IX). Finally, this compound is condensed with ethyl acetimidate (X) in a phosphate buffer.
| 【1】 Tanaka, T.; Sugimura, Y.; Miyadera, T.; Hashimoto, T.; Iino, K.; Shibata, T.; Sugawara, S.; Synthesis and in vitro activity of a new carbapenem, RS-533. J Antibiot 1983, 36, 8, 1034. |
| 【2】 Serradell, M.N.; Castaner, J.; RS-533. Drugs Fut 1985, 10, 12, 989. |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 29845 | benzyl (Z)-3-(1-pyrrolidinyl)-2-butenoate | C15H19NO2 | 详情 | 详情 | |
| (III) | 29846 | benzyl (Z)-4-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-(1-pyrrolidinyl)-2-butenoate | C26H40N2O4Si | 详情 | 详情 | |
| (IV) | 29847 | benzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxobutanoate | C16H19NO5 | 详情 | 详情 | |
| (V) | 29848 | 2-Diazo-4-[3(S)-(1(R)-hydroxyethyl)-4-oxoazetidin-2(R)-yl]-3-oxobutyric acid benzyl ester | C16H17N3O5 | 详情 | 详情 | |
| (VI) | 29849 | benzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H17NO5 | 详情 | 详情 | |
| (VII) | 29850 | 4-nitrobenzyl (3S)-3-sulfanyl-1-pyrrolidinecarboxylate | C12H14N2O4S | 详情 | 详情 | |
| (VIII) | 29851 | benzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S)-1-(4-nitrobenzyl)pyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H29N3O6S | 详情 | 详情 | |
| (IX) | 29852 | (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(3S)pyrrolidinylsulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C13H18N2O4S | 详情 | 详情 | |
| (X) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The cyclization of 3,4-diaminobenzophenone (I) with acetylimidic acid ethyl ester (II) in refluxing methanol gives 5-benzoyl-2-methylbenzimidazole (III), which is reduced with NaBH4 in methanol yielding 5-(alpha-hydroxybenzyl)-2-methylbenzimidazole (IV). Finally, this compound is condensed with imidazole (V) in refluxing acetonitrile.
| 【1】 Raeymaekers, A.H.M.; Freyne, E.J.E.; Sanz, G.C. (Janssen Pharmaceutica NV); Novel (1H-imidazol-1-ylmethyl) substd. benzimidazole derivs. AU 8778385; EP 0260744; JP 1989085975; US 4859684 . |
| 【2】 Castaner, J.; Prous, J.; Irtemazole. Drugs Fut 1991, 16, 12, 1094. |
| 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) | 12830 | (3,4-Diaminophenyl)phenylmethanone; 3,4-Diaminobenzophenone | 39070-63-8 | C13H12N2O | 详情 | 详情 |
| (II) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (III) | 12832 | (2-Methyl-1H-benzimidazol-5-yl)(phenyl)methanone | C15H12N2O | 详情 | 详情 | |
| (IV) | 12833 | (2-Methyl-1H-benzimidazol-5-yl)(phenyl)methanol | C15H14N2O | 详情 | 详情 | |
| (V) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：Condensation of the (3R)-3-pyrrolidinol (I) and the phenylglyoxylate (II) using a procedure described by Bittner gave the (3S)-alpha-keto-ester (III). Wittig reaction of the (3S)-alpha-keto-ester (III) and the phosphonium salts (IV) using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, followed by catalytic hydrogenation gave the ethyl propanoate derivatives (VI) as an equivalent mixture of two diastereoisomers. The mixture (VI) gave the pure (2S,3'S)-isomer (VII) by means of crystallization in ethanol. Pinner synthesis was applied for the single isomer (VII) to give the amidine (VIII). Treatment of the amidine (VIII) with ethyl acetimidate hydrochloride yielded the N-acetimidoyl derivative (IX). Conversion of (IX) to the final product, DX-9065a, was accomplished by acidic hydrolysis followed by crystallization. The absolute configuration of DX-9065a was assigned as (2S,3'S) based on X-ray crystallographic analysis and the (3'S) configuration of the 3 position on the pyrrolidine ring.
| 【1】 Hara, T.; Yamazaki, K.; Nagahara, T.; Kunitada, S.; Katakura, S.; Inamura, K.; Iwamoto, M.; Komoriya, S.; Yokoyama, Y.; DX-9065a. Drugs Fut 1995, 20, 6, 564. |
| 【2】 Iwamoto, M.; Inamura, K.; Nagahara, T.; Komoriya, S.; Hara, T.; Katakura, S.; Yamaguchi, H.; Yokoyama, Y.; Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors. J Med Chem 1994, 37, 8, 1200-7. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 | |
| (I) | 16286 | tert-butyl (3S)-3-hydroxytetrahydro-1H-pyrrole-1-carboxylate | C9H17NO3 | 详情 | 详情 | |
| (II) | 16287 | ethyl 2-(4-hydroxyphenyl)-2-oxoacetate | C10H10O4 | 详情 | 详情 | |
| (III) | 16288 | tert-butyl (3S)-3-[4-(2-ethoxy-2-oxoacetyl)phenoxy]tetrahydro-1H-pyrrole-1-carboxylate | C19H25NO6 | 详情 | 详情 | |
| (IV) | 16289 | 7-[chloro(triphenyl)phosphoranyl]-2-naphthonitrile | C29H21ClNP | 详情 | 详情 | |
| (V) | 16290 | tert-butyl (3S)-3-[4-[(Z)-2-(7-cyano-2-naphthyl)-1-(ethoxycarbonyl)ethenyl]phenoxy]-1-pyrrolidinecarboxylate | C31H32N2O5 | 详情 | 详情 | |
| (VI) | 16291 | tert-butyl (3S)-3-(4-[1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate | C31H32N2O5 | 详情 | 详情 | |
| (VII) | 16292 | tert-butyl (3S)-3-(4-[(1S)-1-[(7-cyano-2-naphthyl)methyl]-2-ethoxy-2-oxoethyl]phenoxy)-1-pyrrolidinecarboxylate | C31H34N2O5 | 详情 | 详情 | |
| (VIII) | 16293 | ethyl (2S)-3-[7-[amino(imino)methyl]-2-naphthyl]-2-[4-[(3S)tetrahydro-1H-pyrrol-3-yloxy]phenyl]propanoate | C26H29N3O3 | 详情 | 详情 | |
| (IX) | 16294 | ethyl (2S)-3-[7-[amino(imino)methyl]-2-naphthyl]-2-(4-[[(3S)-1-ethanimidoyltetrahydro-1H-pyrrol-3-yl]oxy]phenyl)propanoate | C28H32N4O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The reaction of N6-(benzyloxycarbonyl)-N2--(tert-butoxycarbonyl)-L-lysine (I) with 1H-tetrazol-5-amine (II) by means of BOP and DIEA or NMM in DMF gives the corresponding amide (III), which is hydrogenolyzed with H2 over Pd/C in etyhanol/HOAc to yield N2-(tert-butoxycarbonyl)-N1-(1H-tetrazol-5-yl)-L-lysine (IV). The reaction of (IV) with methyl acetimidate (V) by means of TEA in DMF (or ethyl acetimidate (VI) and NaOH in ethanol) affords the iminomethyl derivative (VII), which is finally deprotected with HCl in dioxane.
| 【1】 Hallinan, E.A.; Tsymbalov, S.; Dorn, C.R.; Pitzele, B.S.; Hansen, D.W. Jr.; Synthesis and biological characterization of L-N6-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor. J Med Chem 2002, 45, 8, 1686. |
| 【2】 Hallinan, E.A.; Hansen, D.W. Jr.; Tsymbalov, S. (Pharmacia Corp.); Aminotetrazole derivs. useful as nitric oxide synthase inhibitors. EP 0790987; EP 1113011; JP 1998508847; US 5684008; WO 9615120 . |
| 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) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (III) | 54697 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-oxo-6-(1H-1,2,3,4-tetraazol-5-ylamino)hexylcarbamate | C20H29N7O5 | 详情 | 详情 | |
| (IV) | 54698 | tert-butyl (1S)-5-amino-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C12H23N7O3 | 详情 | 详情 | |
| (V) | 54699 | Methyl ethanimidoate; Methyl acetimidate | C3H7NO | 详情 | 详情 | |
| (VI) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VII) | 54700 | tert-butyl (1S)-5-(ethanimidoylamino)-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C14H26N8O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)4-(Aminomethyl)piperidine (I) was selectively protected at the piperidine N by means of Boc2O. The resultant 1-Boc-4-(aminomethyl)piperidine (II) was condensed with 4-chloro-3-nitropyridine (III) to afford the amino pyridine compound (IV). Catalytic hydrogenation of the nitro group of (IV) furnished the 3,4-diaminopyridine (V), which was cyclized with ethyl acetimidate hydrochloride (VI) to produce the imidazopyridine (VII). Subsequent acid cleavage of the Boc protecting group of (VII) provided the intermediate piperidine (VIII).
| 【1】 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 . |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (III) | 29971 | 4-chloro-3-nitropyridine | C5H3ClN2O2 | 详情 | 详情 | |
| (IV) | 59460 | tert-butyl 4-{[(3-nitro-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H24N4O4 | 详情 | 详情 | |
| (V) | 59461 | tert-butyl 4-{[(3-amino-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H26N4O2 | 详情 | 详情 | |
| (VI) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VII) | 59462 | tert-butyl 4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinecarboxylate | C18H26N4O2 | 详情 | 详情 | |
| (VIII) | 59463 | 2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine | C13H18N4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XXXIII)In a related procedure, chiral oxazoline (XXXV) was prepared by condensation of ethyl acetimidate (XXXIII) with (S,S)-thiomicamine (XXXII), followed by O-methylation with MeI and sodium tert-pentoxide. Condensation of the lithium salt of (XXXV) with diethylchlorophosphate at -78 C provided phosphonate (XXXVI), which was submitted to a Horner-Emmons reaction with pyridine aldehyde (XV) to yield the vinyl oxazoline (XXXVII). Conjugate addition of the organolithium reagent (XXXVIII) to (XXXVII) then produced adduct (XXXIX) as the major diastereoisomer. Hydrolysis of the oxazoline of (XXXIX) upon refluxing in isopropyl alcohol with H2SO4 yielded isopropyl ester (XL). Pyridine carboxylate (XLI) was further obtained by carbonylation of (XL) under atmosphere of CO in the presence of bis(diphenylphosphino)ferrocene and palladium diacetate in MeOH.
| 【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 27563 | 2-bromo-6-butylnicotinaldehyde | C10H12BrNO | 详情 | 详情 | |
| (XXXII) | 27578 | (1S,2S)-2-amino-1-[4-(methylsulfanyl)phenyl]-1,3-propanediol | C10H15NO2S | 详情 | 详情 | |
| (XXXIII) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (XXXIV) | 27579 | [(4S,5S)-2-methyl-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-4-yl]methanol | C12H15NO2S | 详情 | 详情 | |
| (XXXV) | 27580 | (4S,5S)-4-(methoxymethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazole | C13H17NO2S | 详情 | 详情 | |
| (XXXVI) | 27581 | diethyl [(4S,5S)-4-(methoxymethyl)-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-2-yl]methylphosphonate | C17H26NO5PS | 详情 | 详情 | |
| (XXXVII) | 27582 | 2-bromo-6-butyl-3-((E)-2-[(4S,5S)-4-(methoxymethyl)-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-2-yl]ethenyl)pyridine | C23H27BrN2O2S | 详情 | 详情 | |
| (XXXVIII) | 27583 | 1,3-benzodioxol-5-yllithium | C7H5LiO2 | 详情 | 详情 | |
| (XXXIX) | 27584 | [(4S,5S)-2-[(2S)-2-(1,3-benzodioxol-5-yl)-2-(2-bromo-6-butyl-3-pyridinyl)ethyl]-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-4-yl]methyl methyl ether | C30H33BrN2O4S | 详情 | 详情 | |
| (XL) | 27585 | isopropyl (3S)-3-(1,3-benzodioxol-5-yl)-3-(2-bromo-6-butyl-3-pyridinyl)propanoate | C22H26BrNO4 | 详情 | 详情 | |
| (XLI) | 27586 | methyl 3-[(1S)-1-(1,3-benzodioxol-5-yl)-3-isopropoxy-3-oxopropyl]-6-butyl-2-pyridinecarboxylate | C24H29NO6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)Reductive cleavage of L-homocystine (I) with sodium in liquid ammonia produced homocysteine, which was subsequently alkylated with 2-(N-benzyloxycarbonyl-amino)ethyl tosylate (II) to afford thioether (III). The benzyloxycarbonyl protecting group of (III) was cleaved with HBr to give diamine (IV). Finally, condensation with ethyl acetimidate (V) furnished the target amidine.
| 【1】 Young, R.J.; et al.; Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000, 10, 6, 597. |
| 【2】 Beams, R.M.; Frend, A.J.; Drysdale, M.J.; Franzman, K.W.; Hodson, H.F.; Rees, D.D.; Knowles, R.G.; Sawyer, D.A. (Glaxo Wellcome plc); Nitric oxide synthase inhibitors. EP 0958277; JP 2000504041; WO 9830537 . |
| 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) | 42169 | (2S)-2-amino-4-[[(3S)-3-amino-3-carboxypropyl]disulfanyl]butyric acid | C8H16N2O4S2 | 详情 | 详情 | |
| (II) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (III) | 42171 | (2S)-2-amino-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]butyric acid | C14H20N2O4S | 详情 | 详情 | |
| (IV) | 42172 | (2S)-2-amino-4-[(2-aminoethyl)sulfanyl]butyric acid | C6H14N2O2S | 详情 | 详情 | |
| (V) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Claisen condensation of 2,4-dichlorophenylacetonitrile (I) with ethyl acetate using of Na metal gave ketonitrile (II), which was reacted with hydrazine hydrate in the presence of AcOH to afford aminopyrazole (III). Subsequent condensation of (III) with ethyl acetimidate (IV) produced amidine (V). This was cyclized with diethyl carbonate and NaOEt to furnish the pyrazolotriazinone (VI). Chlorination of (VI) using phosphoryl chloride in N,N-dimethylaniline provided chloride (VII), which was finally coupled with 1,3-dimethoxy-2-aminopropane (VIII) to yield the title compound.
| 【1】 Gilligan, P.J.; He, L.; Zaczek, R.; et al.; 4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: A potent, orally bioavailable CRF1 receptor antagonist. J Med Chem 2000, 43, 3, 449. |
| 【2】 Arvanitis, A.G.; Chorvat, R.J. (DuPont Pharmaceuticals Co.); Azolo triazines and pyrimidines. US 6124289; WO 9803510 . |
| 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) | 28484 | 2,4.Dichlorobenzyl cyanide; 2-(2,4-Dichlorophenyl)acetonitrile | 6306-60-1 | C8H5Cl2N | 详情 | 详情 |
| (II) | 28485 | 2-(2,4-dichlorophenyl)-3-oxobutanenitrile | C10H7Cl2NO | 详情 | 详情 | |
| (III) | 27688 | 4-(2,4-dichlorophenyl)-3-methyl-1H-pyrazol-5-amine | C10H9Cl2N3 | 详情 | 详情 | |
| (IV) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (V) | 28486 | N-[4-(2,4-dichlorophenyl)-3-methyl-1H-pyrazol-5-yl]ethanimidamide | C12H12Cl2N4 | 详情 | 详情 | |
| (VI) | 28487 | 8-(2,4-dichlorophenyl)-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one | C13H10Cl2N4O | 详情 | 详情 | |
| (VII) | 28488 | 4-chloro-8-(2,4-dichlorophenyl)-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazine | C13H9Cl3N4 | 详情 | 详情 | |
| (VIII) | 23336 | 1,3-dimethoxy-2-propanamine | C5H13NO2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(V)The condensation of 2,4-dimethoxy-6-methylphenylacetonitrile (I) with ethyl acetate in the presence of Na metal produced keto nitrile (II). This was cyclized to the amino pyrazole (III) upon treatment with hydrazine and HOAc in refluxing toluene. Subsequent condensation of amino pyrazole (III) with ethyl acetimidate (IV) gave amidine (V), which was converted to the required pyrazolo triazinone (VI) by reaction with diethyl carbonate and NaOEt. Chlorination of (VI) with POCl3 in the presence of N,N-dimethylaniline produced the chloro derivative (VII). This was finally condensed with amine (VIII) to furnish the title compound.
| 【1】 He, L.; Arvanitis, A.G.; Chorvat, R.; Gilligan, P. (DuPont Pharmaceuticals Co.); Azolo triazines and pyrimidines. EP 1049699; WO 9938868 . |
| 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) | 43369 | 2-(2,4-dimethoxy-6-methylphenyl)acetonitrile | C11H13NO2 | 详情 | 详情 | |
| (II) | 43370 | 2-(2,4-dimethoxy-6-methylphenyl)-3-oxobutanenitrile | C13H15NO3 | 详情 | 详情 | |
| (III) | 43371 | 4-(2,4-dimethoxy-6-methylphenyl)-3-methyl-1H-pyrazol-5-ylamine; 4-(2,4-dimethoxy-6-methylphenyl)-3-methyl-1H-pyrazol-5-amine | C13H17N3O2 | 详情 | 详情 | |
| (IV) | 43372 | N-[4-(2,4-dimethoxy-6-methylphenyl)-3-methyl-1H-pyrazol-5-yl]ethanimidamide | C15H20N4O2 | 详情 | 详情 | |
| (V) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VI) | 43372 | N-[4-(2,4-dimethoxy-6-methylphenyl)-3-methyl-1H-pyrazol-5-yl]ethanimidamide | C15H20N4O2 | 详情 | 详情 | |
| (VII) | 43373 | 8-(2,4-dimethoxy-6-methylphenyl)-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one | C16H18N4O3 | 详情 | 详情 | |
| (VIII) | 43374 | 4-chloro-8-(2,4-dimethoxy-6-methylphenyl)-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazine; 2-(4-chloro-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-8-yl)-5-methoxy-3-methylphenyl methyl ether | C16H17ClN4O2 | 详情 | 详情 | |
| (IX) | 38928 | (1R)-1-methylpropylamine; (2R)-2-butanamine | C4H11N | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VI)4-(Aminomethyl)piperidine (I) was selectively protected at the piperidine N by means of Boc2O. The resultant 1-Boc-4-(aminomethyl)piperidine (II) was condensed with 4-chloro-3-nitropyridine (III) to afford the amino pyridine compound (IV). Catalytic hydrogenation of the nitro group of (IV) furnished the 3,4-diaminopyridine (V), which was cyclized with ethyl acetimidate hydrochloride (VI), to produce the imidazopyridine (VII). Subsequent acid cleavage of the Boc protecting group of (VII) provided the intermediate piperidine (VIII).
| 【1】 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 . |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (III) | 29971 | 4-chloro-3-nitropyridine | C5H3ClN2O2 | 详情 | 详情 | |
| (IV) | 59460 | tert-butyl 4-{[(3-nitro-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H24N4O4 | 详情 | 详情 | |
| (V) | 59461 | tert-butyl 4-{[(3-amino-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H26N4O2 | 详情 | 详情 | |
| (VI) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VII) | 59462 | tert-butyl 4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinecarboxylate | C18H26N4O2 | 详情 | 详情 | |
| (VIII) | 59463 | 2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine | C13H18N4 | 详情 | 详情 |