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【结 构 式】 
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【分子编号】23944 【品名】1-Hydrazinecarboxamide 【CA登记号】563-41-7 |
【 分 子 式 】CH5N3O 【 分 子 量 】75.07032 【元素组成】C 16% H 6.71% N 55.97% O 21.31% |
合成路线1
该中间体在本合成路线中的序号：(A)The cyclization of 17alpha-azido-3beta,16alpha-acetoxy-5alpha-pregnane-11,20-dione (I) by hydrogenation with H2 over Pt in methanol, followed by a treatment with 10% HCl gives 3beta-hydroxy-5alpha-pregnane-11,20-dione-[17alpha,16alpha-d]-2'-methyloxazoline (II), which is converted into the semicarbazone (III) by treatment with semicarbazide hydrochloride (A) and pyridine in refluxing methanol. The reduction of one ketonic group of (III) with NaBH4 in refluxing ethanol yields the dihydroxy-semicarbazone (IV), which is hydrolyzed with 10% HCl in refluxing methanol to afford the ketodiol (V). The oxidation of (V) with cyclohexanone and aluminum isopropoxide in refluxing toluene gives 11beta-hydroxy-5alpha-pregnane-3,20-dione-[17alpha,16alpha-d]-2'-methyloxazoline (VI). The dehydrogenation of (VI) by treatment with Br2 in dioxane-acetic acid, followed by treatment with Li2CO3 in DMF at 140 C yields the corresponding 1,4-diene derivative (VII). Finally, the reaction of (VII) with I2 by means of azobisisobutyronitrile in CH2Cl2 affords the corresponding 21-iodo compound, which is then acetylated with triethylammonium acetate in refluxing acetone.
| 【1】 Nathansohn, G.; et al.; Steroids possessing nitrogen atoms. III. Synthesis of new highly active corticoids [17alpha,16alpha-d]-ozazolino steroids. J Med Chem 1967, 10, 5, 799. |
| 【2】 Castaner, J.; de Angelis, L.; Aclacinomycin A. Drugs Fut 1978, 3, 3, 171. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (I) | 33511 | (3R,8S,9S,10S,13S,14S,16R,17S)-17-acetyl-16-(acetoxy)-17-azido-10,13-dimethyl-11-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate; 17alpha-azido-3beta,16alpha-acetoxy-5alpha-pregnane-11,20-dione | 5167-90-8 | C25H35N3O6 | 详情 | 详情 |
| (II) | 33512 | 3beta-hydroxy-5alpha-pregnane-11,20-dione-[17alpha,16alpha-d]-2'-methyloxazoline; (2R,4aS,4bS,6aS,6bS,9aR,10aS,10bS)-6b-acetyl-2-hydroxy-4a,6a,8-trimethyl-1,2,3,4,4a,4b,6,6a,6b,9a,10,10a,10b,11,12,12a-hexadecahydro-5H-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-5-one | 5070-98-4 | C23H33NO4 | 详情 | 详情 |
| (III) | 33513 | 2-[(Z)-1-[(2R,4aS,4bS,6aS,9aR,10aS,10bS)-2-hydroxy-4a,6a,8-trimethyl-5-oxo-1,2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12,12a-hexadecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-6-yl]ethylidene]-1-hydrazinecarboxamide | C24H36N4O4 | 详情 | 详情 | |
| (IV) | 33514 | 2-[(Z)-1-[(2R,4aS,4bS,5S,6aS,9aR,10aS,10bS)-2,5-dihydroxy-4a,6a,8-trimethyl-1,2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12,12a-hexadecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-6-yl]ethylidene]-1-hydrazinecarboxamide | C24H38N4O4 | 详情 | 详情 | |
| (V) | 33515 | 1-[(2R,4aS,4bS,5S,6aS,9aR,10aS,10bS)-2,5-dihydroxy-4a,6a,8-trimethyl-1,2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12,12a-hexadecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-6-yl]-1-ethanone | 13649-86-0 | C23H35NO4 | 详情 | 详情 |
| (VI) | 33516 | (4aS,4bS,5S,6aS,6bS,9aR,10aS,10bS)-6b-acetyl-5-hydroxy-4a,6a,8-trimethyl-1,3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12,12a-hexadecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-2-one; 11beta-hydroxy-5alpha-pregnane-3,20-dione-[17alpha,16alpha-d]-2’-methyloxazoline | C23H33NO4 | 详情 | 详情 | |
| (VII) | 33517 | (4aR,4bS,5S,6aS,6bS,9aR,10aS,10bS)-6b-acetyl-5-hydroxy-4a,6a,8-trimethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-2-one | 13649-88-2 | C23H29NO4 | 详情 | 详情 |
| (VIII) | 33518 | (4aR,4bS,5S,6aS,6bS,9aR,10aS,10bS)-5-hydroxy-6b-(2-iodoacetyl)-4a,6a,8-trimethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]oxazol-2-one | C23H28INO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)In an alternative method, condensation of semicarbazide hydrochloride (I) with cyclohexanone (II) yields the semicarbazone (III). Subsequent reaction of (III) with ethyl chloroacetate (IV) in the presence of NaOMe gives rise to the cyclohexylidene aminohydantoin (V). Treatment of (V) with 5-(p-nitrophenyl)furfural (VI) under acidic conditions affords the furfurylidene aminohydantoin (VII). This is finally converted into the corresponding sodium salt employing methanolic NaOMe (3).
| 【1】 Martin-Escudero Perez, U.; Izquierdo Sanjose, M.; Process for obtaining 1-[(5-(p-nitrophenyl)furfuryliden)amino]hydantoin and its sodium salt. ES 458000 . |
| 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) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (III) | 63587 | 2-cyclohexylidene-1-hydrazinecarboxamide | C7H13N3O | 详情 | 详情 | |
| (IV) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (V) | 63588 | 1-(cyclohexylideneamino)-2,4-imidazolidinedione | C9H13N3O2 | 详情 | 详情 | |
| (VI) | 63583 | 5-(4-nitrophenyl)-2-furaldehyde | C11H7NO4 | 详情 | 详情 | |
| (VII) | 63586 | 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione | C14H10N4O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)The reaction of 2-chloro-4-cyanopyridine (I) with sodium methoxide in refluxing methanol gives 2-methoxy-4-cyanopyridine (II), which by reduction with H2 over Raney-Ni and semicarbazide HCl in water-ethanol is converted to 2-methoxypyridine-4-carboxyaldehyde (III). The condensation of (III) with malonic acid (IV) by means of piperidine in hot pyridine yields 3-(2-methoxy-4-pyridyl)acrylic acid (V), which is esterified with ethanol and H2SO4 to the ethyl ester (VI). The reduction of (VII) with H2 over Pd/C in ethanol affords the corresponding propionate (VII). Formylation of (VII) with ethyl formate and NaH gives ethyl 2-formyl-3-(2-methoxy-4-pyridyl)propionate (VIII), which is cyclized with nitroguanidine (IX) by means of sodium methoxide in refluxing methanol yielding 2-nitroamino-5-12-methoxy-4-pyridylmethylpyrimidin-4(1H)-one (X). The reaction of (X) with 2-[5-(dimethylaminomethyl)-2 furylmethylthio]ethylamine in refluxing ethanol gives the O-methyl derivative of SK&F 93574 (XII), whicn is finally deprotected with HCl in refluxing ethanol.
| 【1】 Brown, T.H.; Ife, R.J. (SmithKline Beecham plc); Pyrimidine compounds. DD 140252; EP 0003677; ES 477667; US 4234588; US 4649141 . |
| 【2】 Adger, B.M.; Lewis, N.J. (SmithKline Beecham plc); Chemical process. EP 0141560 . |
| 【3】 Prous, J.; Castaner, J.; SK&F-93574. Drugs Fut 1986, 11, 8, 671. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (I) | 23940 | 2-Chloro-4-pyridinecarbonitrile; 2-chloroisonicotinonitrile | 33252-30-1 | C6H3ClN2 | 详情 | 详情 |
| (II) | 23943 | 2-methoxyisonicotinonitrile | C7H6N2O | 详情 | 详情 | |
| (III) | 23941 | 2-methoxyisonicotinaldehyde | C7H7NO2 | 详情 | 详情 | |
| (IV) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (V) | 23945 | (Z)-3-(2-methoxy-4-pyridinyl)-2-propenoic acid | C9H9NO3 | 详情 | 详情 | |
| (VI) | 23946 | ethyl (Z)-3-(2-methoxy-4-pyridinyl)-2-propenoate | C11H13NO3 | 详情 | 详情 | |
| (VII) | 23947 | ethyl 3-(2-methoxy-4-pyridinyl)propanoate | C11H15NO3 | 详情 | 详情 | |
| (VIII) | 23948 | ethyl 2-formyl-3-(2-methoxy-4-pyridinyl)propanoate | C12H15NO4 | 详情 | 详情 | |
| (IX) | 23949 | N2-Nitroguanidine | CH4N4O2 | 详情 | 详情 | |
| (X) | 23950 | 5-(2-Methoxypyridin-4-yl)-2-(nitroamino)pyrimidin-4(1H)-one | C11H11N5O4 | 详情 | 详情 | |
| (XI) | 13851 | 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine | C10H18N2OS | 详情 | 详情 | |
| (XII) | 23951 | 2-([2-[([5-[(dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]amino)-5-[(2-methoxy-4-pyridinyl)methyl]-4(1H)-pyrimidinone | C21H27N5O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation of 3'-chloro-4'-cyclohexylacetophenone (I) with semicarbazide hydrochloride (II) produced the semicarbazone (III). Treatment of (III) with selenium dioxide in HOAc generated the intermediate selenodiazole (IV) which, on further heating, gave rise to the aryl acetylene (V). Cupric chloride-catalyzed Mannich condensation of acetylene (V) with N-ethyl cyclohexylamine (VI) and formaldehyde yielded the propargyl amine (VII). Partial hydrogenation of the triple bond of (VII) using the Lindlar catalyst provided the target (Z)-propenyl amine, which was finally converted to the hydrochloride salt.
| 【1】 Breliere, J.-C.; Casellas, P.; Lavastre, S.; Paul, R. (Sanofi-Synthelabo); Benzene derivates, their preparation and pharmaceutical compsns. containing them. EP 0376850; FR 2641276; JP 1991002116; US 5354781 . |
| 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) | 59241 | 1-(3-chloro-4-cyclohexylphenyl)-1-ethanone | C14H17ClO | 详情 | 详情 | |
| (II) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (III) | 59242 | 2-[(E)-1-(3-chloro-4-cyclohexylphenyl)ethylidene]-1-hydrazinecarboxamide | C15H20ClN3O | 详情 | 详情 | |
| (IV) | 59243 | 4-(3-chloro-4-cyclohexylphenyl)-1,2,3-selenadiazole | C14H15ClN2Se | 详情 | 详情 | |
| (V) | 59244 | 2-chloro-1-cyclohexyl-4-ethynylbenzene | C14H15Cl | 详情 | 详情 | |
| (VI) | 59245 | N-Ethylcyclohexanamine; N-Ethylcyclohexylamine; Vulkacit HX | 5459-93-8 | C8H17N | 详情 | 详情 |
| (VII) | 59246 | N-[3-(3-chloro-4-cyclohexylphenyl)-2-propynyl]-N-cyclohexyl-N-ethylamine; N-[3-(3-chloro-4-cyclohexylphenyl)-2-propynyl]-N-ethylcyclohexanamine | C23H32ClN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Condensation of 4-fluorophenol (I) with 4-fluorobenzaldehyde (II) by heating with K2CO3 in N,N-dimethylacetamide provides 4-(4-fluorophenoxy)benzaldehyde (III), which is finally converted into the target product by reaction with semicarbazide hydrochloride (IV) and NaOAc in the refluxing mixture EtOH/H2O.
| 【1】 Lam, G.N.; Ramu, K.; Chien, B.; Development of a high-performance liquid chromatographic-tandem mass spectrometric method for the determination of pharmacokinetics of Co 102862 in mouse, rat, monkey and dog plasma. J Chromatogr B - Biomed Appl 2000, 749, 1, 1. |
| 【2】 Quail, J.W.; Dimmock, J.R.; Puthucode, R.N.; Pugazhenthi, U.; Stables, J.P.; Anticonvulsant activity of various aryl, aryldine and aryloxyaryl semicarbazones. Eur J Med Chem 1998, 33, 7-8, 595. |
| 【3】 Dimmock, J.R.; Puthucode, R.N. (University of Saskatchewan); Semicarbazones having CNS activity and pharmaceutical preparations containing same. EP 0836591; JP 1999506109; US 5741818; WO 9640628 . |
合成路线6
该中间体在本合成路线中的序号：(XXVII)Synthesis of 250157: Alternatively, the final compound can be obtained by direct condensation of (VI) with chlorotriazolinone (XXVI) in DMF/H2O in the presence of K2CO3 or DIEA. For the obtention of (XXVI), two routes can be followed: 1. Reaction of semicarbazide (XXVII) with orthoester (XXVIII) in MeOH; and 2. Condensation of semicarbazide (XXVII) with benzyloxyacetyl chloride (XXIX) in THF/H2O in the presence of NaOH to provide adduct (XXX), which is then cyclized by means of refluxing NaOH to afford triazolinone (XXXI). Debenzylation of (XXXI) by hydrogenation over Pd/C in MeOH/H2O yields alcohol (XXXII), which is finally treated with thionyl chloride.
| 【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211. |
| 【2】 Cowden, C.J.; et al.; A new synthesis of 1,2,4-triazolin-5-ones: Application to the convergent synthesis of an NK1 antagonist. Tetrahedron Lett 2000, 41, 44, 8661. |
| 【3】 Cowden, C.J. (Merck Sharp & Dohme Ltd.); Process for the preparation of 1,2,4-triazolin-5-one derivs.. WO 0196315 . |
| 【4】 Dolling, U.H.; Wilson, R.D.; Hands, D.; Cottrell, I.F. (Merck Sharp & Dohme Ltd.); Chemical synthesis of morpholine derivs.. WO 9965900 . |
| 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) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (XXVI) | 44196 | 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C3H4ClN3O | 详情 | 详情 | |
| (XXVII) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (XXVIII) | 44197 | 2-chloro-1,1-dimethoxyethyl methyl ether; 2-chloro-1,1,1-trimethoxyethane | C5H11ClO3 | 详情 | 详情 | |
| (XXIX) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XXX) | 44193 | 2-[2-(benzyloxy)acetyl]-1-hydrazinecarboxamide | C10H13N3O3 | 详情 | 详情 | |
| (XXXI) | 44194 | 5-[(benzyloxy)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C10H11N3O2 | 详情 | 详情 | |
| (XXXII) | 44195 | 5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C3H5N3O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The compound was prepared by solid-phase synthesis. Condensation of tert-butyl carbazate (I) with 1,1'-carbonyldiimidazole (II) afforded the acyl imidazole (III). Coupling of (III) with amino resin produced the Boc-protected semicarbazide-linked resin (IV), which was deprotected with trifluoroacetic acid to give (V). Condensation of (V) with protected L-argininal (VI) provided the semicarbazone resin (VII). Further solid-phase peptide synthesis by means of sequential coupling with L-alanine, D-serine and phenethylsulfonyl chloride yielded the peptide-resin (VIII). Finally, deprotection of both Boc groups of (VIII) with concomitant resin cleavage by means of aqueous trifluoroacetic acid furnished the target compound.
| 【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090. |
| 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) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (II) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (III) | 29391 | tert-butyl 2-(1H-imidazol-1-ylcarbonyl)-1-hydrazinecarboxylate | C9H14N4O3 | 详情 | 详情 | |
| (IV) | 29392 | tert-butyl 2-(aminocarbonyl)-1-hydrazinecarboxylate | C6H13N3O3 | 详情 | 详情 | |
| (V) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (VI) | 29393 | 9H-fluoren-9-ylmethyl (1S)-4-([[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]amino)-1-formylbutylcarbamate | C31H40N4O7 | 详情 | 详情 | |
| (VII) | 29394 | tert-butyl (Z)-[((4S)-5-[(E)-2-(aminocarbonyl)hydrazono]-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]pentyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C32H43N7O7 | 详情 | 详情 | |
| (VIII) | 29395 | tert-butyl (Z,6S,9S,12R)-6-[[(E)-2-(aminocarbonyl)hydrazono]methyl]-1-[(tert-butoxycarbonyl)amino]-12-(hydroxymethyl)-9-methyl-8,11,14,14-tetraoxo-16-phenyl-14lambda(6)-thia-2,7,10,13-tetraazahexadec-1-ylidenecarbamate | C31H51N9O10S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The title semicarbazone was synthesized by condensation of 2-undecenal (I) with semicarbazide hydrochloride (II) in the presence of NaOAc in aqueous EtOH.
| 【1】 Vashishtha, S.C.; Dimmock, J.R.; Stables, J.P.; Anticonvulsant properties of various acetylhydrazones, oxamoylhydrazones and semicarbazones derived from aromatic an unsaturated carbonyl compounds. Eur J Med Chem 2000, 35, 2, 241. |