|
【结 构 式】 
|
【分子编号】15113 【品名】cyclopentanone 【CA登记号】120-92-3 |
【 分 子 式 】C5H8O 【 分 子 量 】84.11792 【元素组成】C 71.39% H 9.59% O 19.02% |
合成路线1
该中间体在本合成路线中的序号：(II)9alpha,fluoro-11beta16alpha,17,21-tetrahydroxypregna-1,4-diene-3,20-dione (I) is ketalized by reaction with cyclopentanone (II) by means of perchloric acid yielding the ketal (III), which is then acetylated by reaction with acetic anhydride in pyridine.
| 【1】 Hillier, K.; Castaner, J.; Amcinodine. Drugs Fut 1978, 3, 5, 337. |
| 【2】 Sieger, G.M.; Krieger, C. (American Cyanamid Co.); Administration of 16alpha,17alpha-cyclopentylidenedioxy-9alpha-fluoro-11beta,21-dihydroxy-1,4-pregnadiene-3,20-dione-21-acetate. DE 2437847; FR 2240738; GB 1442925; US 4158055 . |
| 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) | 39959 | (8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | 124-94-7 | C21H27FO6 | 详情 | 详情 |
| (II) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (III) | 39960 | triamcinolone cyclopentanonide | 55646-99-6 | C26H33FO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Treatment of ethyl cyanoacetate derivative (I) with cyanoacetamide (II) in EtOH in the presence of NaOEt provides dicyano derivative (III), which is then converted into diimide (IV) by treatment with refluxing sulfuric acid. Alternatively, (IV) can also be obtained by reaction between cyclopentanone (V), cyanoacetamide (II) and piperidine by means of KOH or NaOH in H2O (or H2O/EtOH) to provide mononitrile derivative (VI), which is then refluxed with H2SO4. Double N-alkylation of compound (IV) with chloride (VII) by heating with NaH or alkaline carbonate in DMF yields dialkylated compound (VIII), which is reduced with LiAlH4 or Red-Al in refluxing THF/toluene to furnish the free base (IX). Finally, (IX) is converted into the desired dihydrochloride by treatment with HCl in isopropanol.
| 【1】 McElvain, S.M.; Clemens, D.H.; Piperidine derivatives. XXX. 1,4-Dialkyl-4-arylpiperidines. J Am Chem Soc 1958, 80, 3915. |
| 【2】 Thole, F.B.; Thorpe, J.F.; The formation and reactions of imino-compounds. Part XV. The production of imino-derivatives of piperidine leading to the formation of the betabeta-disubstituted glutaric acids. J Chem Soc 1911, 99, 422. |
| 【3】 Schon, U.; et al.; Synthesis, pharmacological characterization, and quantitative structure-activity relationship analyses of 3,7,9,9-tetraalkylbispidines: Derivatives with specific bradycardic activity. J Med Chem 1998, 41, 3, 318. |
| 【4】 Shon, U.; Hachmeister, B.; Kehrbach, W.; Kuhl, U.; Buschmann, G. (Kali-Chemie AG); New 3,7-diazabicylo[3.3.1]nonanes. DE 3234697; EP 0103833; JP 1993247039 . |
| 【5】 Schon, U.; Heitmann, W.; Matzel, U. (Kali-Chemie AG); Medicament containing crystalline fumaric acid salts or 9,9-alkylen-3-7-diazabicyclononane cpds.. DE 4139763; EP 0550383; JP 1993247040 . |
| 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) | 43191 | ethyl 2-cyano-2-cyclopentylideneacetate | 5407-83-0 | C10H13NO2 | 详情 | 详情 |
| (II) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (III) | 49455 | 7,9-Dioxo-8-azaspiro[4.5]decane-6,10-dicarbonitrile | C11H11N3O2 | 详情 | 详情 | |
| (IV) | 49456 | C11H12N2O4 | 详情 | 详情 | ||
| (V) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (VI) | 49457 | 10-cyano-7-imino-9-oxo-8-azaspiro[4.5]decane-6-carboxamide | C11H14N4O2 | 详情 | 详情 | |
| (VII) | 29776 | 1-(chloromethyl)cyclopropane | 5911-08-0 | C4H7Cl | 详情 | 详情 |
| (VIII) | 49458 | C19H24N2O4 | 详情 | 详情 | ||
| (IX) | 49459 | C19H32N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(B)The synthesis of bervastatin is outlined: Heating of 2-hydroxyacetophenone (A) with cyclopentanone (B) and pyrrolidine in toluene gave 3,4-dihydrospiro[1-benzopyran-2(2H),1'-cyclopentan]-4-one (I). 1,2-Addition of 4-fluorophenylmagnesium bromide (D) on (I) followed by dehydration of the intermediate alcohol (II) upon treatment with p-toluenesulfonic acid yielded 4-(4-fluorophenyl)spiro[1-benzopyran-2(2H),1'-cyclopentane] (III). Vilsmeier reaction on (III) using 3-morpholinoacrolein (E) gave the corresponding prop-2-enal (IV). Addition of the dianion of ethyl acetoacetate to aldehyde (IV) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (V) with diethylmethoxyborane and sodium borohydride yielded bervastatin.
| 【1】 Festal, D.; Bervastatin. Drugs Fut 1995, 20, 12, 1217. |
| 【2】 Festal, D.; Nioche, J.-Y.; Descours, D.; Bellemin, R.; Decerprit, J. (Lipha Santé); Derivs. of benzocycloalkenyldihydroxyalkanoic acids, inhibitors of HMG-CoA reductase, antagonists of thromboxane A2 receptors and antifungals. AU 9048797; EP 0380392; FR 2642065; JP 1990258738; US 5082859; US 5183924 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (B) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (A) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (E) | 44198 | (E)-3-(4-morpholinyl)-2-propenal | C7H11NO2 | 详情 | 详情 | |
| (I) | 14114 | 3,4-Dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-one | C13H14O2 | 详情 | 详情 | |
| (II) | 14115 | 4-(4-Fluorophenyl)-3,4-dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-ol | C19H19FO2 | 详情 | 详情 | |
| (III) | 14116 | 4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentane] | C19H17FO | 详情 | 详情 | |
| (IV) | 14117 | 3-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-2(E)-propenal | C22H19FO2 | 详情 | 详情 | |
| (V) | 14118 | 5-Hydroxy-7-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-3-oxo-6(E)-heptenoic acid ethyl ester | C28H29FO5 | 详情 | 详情 | |
| (C) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)This compound can be obtained by two related ways: The reaction of cyclopentanone (I) with ethyl cyanoacetate (II) by means of HOAc/NH4OAc gives the cyclopentylidene derivative (III), which by reaction with KCN yields 1-(cyanomethyl)cyclopentanecarbonitrile (IV). The hydrolysis of (IV) with HCl affords the dicarboxylic acid (V), which by reaction with Ac2O affords the corresponding cyclic anhydride (VI). Finally, the reaction of (VI) with O-benzyl hydroxylamine hydrochloride and NaHCO3 provides the target compound. Alternatively, the cyclic anhydride (VI) is treated with hydroxylamine hydrochloride and Na2CO3 to gives the N-hydroxyimide (VIII), which is converted into its sodium salt (IX) by means of NaOEt in EtOH, and finally alkylated with benzyl chloride (X) to provide the target compound.
| 【1】 Scott, K.R.; Nicholson, J.M.; Edafiogho, I.O.; Farrar, V.A.; Hinko, C.N.; Moore, J.A.; Imidooxy anticonvulsants: Structural analogs with special emphasis on N-(benzyloxy)-2-azaspiro[4,4]nonane-1,3-dione. Drugs Fut 1992, 17, 5, 395. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 43191 | ethyl 2-cyano-2-cyclopentylideneacetate | 5407-83-0 | C10H13NO2 | 详情 | 详情 |
| (IV) | 43192 | 1-(cyanomethyl)cyclopentanecarbonitrile | C8H10N2 | 详情 | 详情 | |
| (V) | 43193 | 1-(carboxymethyl)cyclopentanecarboxylic acid | C8H12O4 | 详情 | 详情 | |
| (VI) | 27158 | 2-oxaspiro[4.4]nonane-1,3-dione | C8H10O3 | 详情 | 详情 | |
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 43194 | 2-hydroxy-2-azaspiro[4.4]nonane-1,3-dione | C8H11NO3 | 详情 | 详情 | |
| (IX) | 43195 | sodium 1,3-dioxo-2-azaspiro[4.4]nonan-2-olate | C8H10NNaO3 | 详情 | 详情 | |
| (X) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of cyclopentanone (I) with sodium cyanide, NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II), which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III). The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V), which, without isolation, is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI). This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene. The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X). Cyclization of (X) with tributyltin azide in refluxing xylene, followed by reaction with trityl chloride in DMF, affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI). Finally, this compound is hydrolyzed to irbesartan with HCl in methanol/THF. The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.
| 【1】 Casas, A.; Merlos, M.; Castaner, J.; Irbesartan. Drugs Fut 1997, 22, 5, 481. |
| 【2】 Bernhart, C.; Breliere, J.-C.; Clement, J.; Nisato, D.; Perreaut, P. (Sanofi-Synthélabo ); Heterocyclic N-substd. derivs., their preparation and the pharmaceutical compsns. containing them. EP 0454511; FR 2659967; FR 2665702; JP 1992506222; JP 1998279566; US 5270317; WO 9114679 . |
| 【3】 Caron, A.; Chantreux, D.; Bouloumie, C. (Sanofi-Synthelabo ); Method for the preparation of a tetrazole deriv. under two crystalline forms and novel crystalline form of this deriv. EP 0708103 . |
| 【4】 Bernhart, C.A.; Perreaut, P.M.; Ferrari, B.P.; et al.; A new series of imidazolones: Highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists. J Med Chem 1993, 36, 22, 3371-80. |
| 【5】 Bernhart, C.; Clement, J.; Ferrari, B.; et al.; Spiro-dihydro-imidazolones, a new class of non-peptide angiotensin II receptor antagonists. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-084.A.. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (II) | 15114 | 1-aminocyclopentanecarbonitrile | C6H10N2 | 详情 | 详情 | |
| (III) | 15115 | 1-Amino-1-cyclopentane carboxamide; 1-Aminocyclopentanecarboxamide | 17193-28-1 | C6H12N2O | 详情 | 详情 |
| (IV) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (V) | 15117 | N-[1-(aminocarbonyl)cyclopentyl]pentanamide; 1-(pentanoylamino)cyclopentanecarboxamide | C11H20N2O2 | 详情 | 详情 | |
| (VI) | 15118 | 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 1,3-Diazaspirol[4,4]non-1-en-4-one,2-butyl | 151257-01-1 | C11H18N2O | 详情 | 详情 |
| (VII) | 15119 | ethyl 1-aminocyclopentanecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (VIII) | 15120 | ethyl pentanimidoate | C7H15NO | 详情 | 详情 | |
| (IX) | 15332 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl | 114772-54-2 | C14H10BrN | 详情 | 详情 |
| (X) | 15122 | 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl][1,1'-biphenyl]-2-carbonitrile | C25H27N3O | 详情 | 详情 | |
| (XI) | 15121 | 2-butyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one | C44H42N6O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Reaction of triethyl orthopropionate (I) with malononitrile (II) at reflux temperature provided (1-ethoxypropylidene)malononitrile (III). Cyclopentanone (IV) was condensed with tert-butyl carbazate (V) to afford the corresponding hydrazone (VI). Subsequent reduction with sodium cyanoborohydride, followed by acid deprotection furnished cyclopentylhydrazine (VII). Then, condensation of (VII) with malononitrile derivative (III) produced pyrazole (VIII). Partial hydrolysis of the cyano group of (VIII) using concentrated sulfuric acid gave carboxamide (IX).
| 【1】 Bacon, E.R.; Singh, B.; Lesher, G.Y.; Lesher, L.E. (Sanofi-Synthelabo); 6-Heterocyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compsns. and method of use. US 5294612 . |
| 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) | 10395 | 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate | 115-80-0 | C9H20O3 | 详情 | 详情 |
| (II) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (III) | 26907 | 2-(1-ethoxypropylidene)malononitrile | C8H10N2O | 详情 | 详情 | |
| (IV) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (V) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (VI) | 26908 | tert-butyl 2-cyclopentylidene-1-hydrazinecarboxylate | C10H18N2O2 | 详情 | 详情 | |
| (VII) | 26909 | 1-cyclopentylhydrazine | C5H12N2 | 详情 | 详情 | |
| (VIII) | 26910 | 5-amino-1-cyclopentyl-3-ethyl-1H-pyrazole-4-carbonitrile | C11H16N4 | 详情 | 详情 | |
| (IX) | 26911 | 5-amino-1-cyclopentyl-3-ethyl-1H-pyrazole-4-carboxamide | C11H18N4O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Treatment of ethyl N-Boc-(S)-pyroglutamate (I) with lithium hexamethyldisilazide in THF at -78 C, followed by aldol condensation of the resulting lithium enolate with cyclopentanone (II) in the presence of boron trifluoride etherate, furnished adduct (III). Dehydration of the alcohol group of (III) to produce olefin (IV) was achieved by treatment of (III) with methanesulfonyl chloride and triethylamine. Hydrolysis of the ester and lactam groups of (IV) by means of LiOH afforded diacid (V). The N-Boc group of (V) was finally cleaved with HCl in EtOH.
| 【1】 Bleakman, D.; Ezquerra, J.; Baker, S.R.; et al.; 4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists. Bioorg Med Chem Lett 2000, 10, 16, 1807. |
| 【2】 Rubio Esteban, A.; Pedregal Tercero, C. (Lilly SA); Glutamic acid derivs. and pharmaceutical compsns. for the treatment of central nervous system disorders. EP 0867430; ES 2133095; JP 1998279542 . |
| 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) | 43914 | 1-(tert-butyl) 2-ethyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate | 144978-35-8 | C12H19NO5 | 详情 | 详情 |
| (II) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (III) | 43915 | 1-(tert-butyl) 2-ethyl (2S)-4-(1-hydroxycyclopentyl)-5-oxo-1,2-pyrrolidinedicarboxylate | C17H27NO6 | 详情 | 详情 | |
| (IV) | 43916 | 1-(tert-butyl) 2-ethyl (2S)-4-cyclopentylidene-5-oxo-1,2-pyrrolidinedicarboxylate | C17H25NO5 | 详情 | 详情 | |
| (V) | 43917 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-cyclopentylidenepentanedioic acid | C15H23NO6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)The reaction of benzohydroxamic acid (I) with benzyl bromide (II) by means of NaOH on ethanol gives the corresponding benzyl ester (III), which is treated with HCl yielding O-benzylhydroxylamine (IV). The reaction of (IV) with dicyaniamide (V) in ethanol affords the biguanide (VI), which is cyclized with cyclopentanone (VII) and HCl giving 1-benzyloxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (VIII). The debenzylation of (VIII) with H2 over PtO2 in ethanol yields 1-hydroxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (IX), which is finally condensed with 1,6-dibromohexane (X) by means of NaOH in methanol.
| 【1】 Zhang, X.P.; Shen, J.; Xin, Z.M.; Qiu, Q.P.; Zhou, W.C.; Synthesis and antiprotozoal activities of some new triazine derivatives including a new antitrypanosomal agent: SIPI-1029. Acta Pharm Sin 1996, 31, 11, 823. |
| 【2】 Zhou, W.; Zhang, X.; Trybizine Hydrochloride. Drugs Fut 1999, 24, 10, 1084. |
| 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) | 24777 | N-hydroxybenzamide | 495-18-1 | C7H7NO2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 24779 | N-(benzyloxy)benzamide | C14H13NO2 | 详情 | 详情 | |
| (IV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (V) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
| (VI) | 24782 | 1-[([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)methyl]benzene | C9H13N5O | 详情 | 详情 | |
| (VII) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (VIII) | 24784 | 10-(benzyloxy)-6,8,10-triazaspiro[4.5]deca-6,8-diene-7,9-diamine | C14H19N5O | 详情 | 详情 | |
| (IX) | 24785 | 7,9-diamino-6,8,10-triazaspiro[4.5]deca-7,9-dien-6-ol | C7H13N5O | 详情 | 详情 | |
| (X) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VII)The reaction of benzohydroxamic acid (I) with 1,6-dibromohexane (X) by means of NaOH in methanol gives the bis benzohydroxamic ester (XI), which is treated with HCl to afford the subituted bis hydroxylamine (XII). The reaction of (XII) with dicyandiamide (V) in ethanol yields the bis biguanide (XIII), which is finally cyclized with cyclopentanone (VII) and HCl as before.
| 【1】 Zhang, X.P.; Shen, J.; Xin, Z.M.; Qiu, Q.P.; Zhou, W.C.; Synthesis and antiprotozoal activities of some new triazine derivatives including a new antitrypanosomal agent: SIPI-1029. Acta Pharm Sin 1996, 31, 11, 823. |
| 【2】 Zhou, W.; Zhang, X.; Trybizine Hydrochloride. Drugs Fut 1999, 24, 10, 1084. |
| 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) | 24777 | N-hydroxybenzamide | 495-18-1 | C7H7NO2 | 详情 | 详情 |
| (V) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
| (VII) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (X) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (XI) | 24787 | N-([6-[(benzoylamino)oxy]hexyl]oxy)benzamide | C20H24N2O4 | 详情 | 详情 | |
| (XII) | 24788 | 1,6-bis(aminooxy)hexane | C6H16N2O2 | 详情 | 详情 | |
| (XIII) | 24789 | 1,6-bis([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)hexane | C10H24N10O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IX)N-Demethylation by treatment with iodine and sodium acetate under irradiation of a halogen lamp produced secondary amine (VIII). Finally, reductive condensation of (VIII) with cyclopentanone (IX) in the presence of sodium cyanoborohydride yielded the title cyclopentylamino compound.
| 【1】 Kaminski, M.A.; Crawford, B.W.; Dalton, C.R.; Mort, N.A.; Sauer, D.R.; Bruncko, M.; Greer, J.; Frey, L.M.; Randolph, J.; Haviv, F. (Abbott Laboratories Inc.); Macrolide LHRH antagonists. US 5955440; WO 9950275 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 33677 | (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3,4-dichlorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione | C47H74Cl2N2O13 | 详情 | 详情 | |
| (VIII) | 33679 | (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3,4-dichlorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-10-[[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione | C46H72Cl2N2O13 | 详情 | 详情 | |
| (IX) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)Aminonitrile (II) was prepared by Strecker reaction of cyclopentanone (I) with potassium cyanide and dimethylamine hydrochloride. Subsequent reduction of (II) with alane, generated in situ from LiAlH4 and H2SO4, produced diamine (III).
| 【1】 Caulfield, W.L.; et al.; The first potent and selective inhibitors of the glycine transporter type 2. J Med Chem 2001, 44, 17, 2679. |
合成路线12
该中间体在本合成路线中的序号：(III)Indole (I) is protected as the indole N-carboxylate (II) by treatment of its lithio derivative with carbon dioxide gas in cold THF. Subsequent metalation with tert-butyllithium, followed by addition to cyclopentanone (III) gives rise to the carbinol adduct (IV). Dehydration of (IV) under acidic conditions furnishes 2-(1-cyclopentenyl)indole (V). Diels-Alder condensation of (V) with maleimide (VI) at 190 C provides the pentacyclic system (VII). Further dehydrogenation of (VII) employing DDQ leads to the fused carbazole compound (VIII). Regioselective halogenation of (VIII) at position 3 by means of NBS yields the corresponding aryl bromide (IX). Then, displacement of the bromide group of (IX) with either CuCN or Zn(CN)2 produces nitrile (X). This is finally reduced to the primary amine by catalytic hydrogenation in the presence of Raney nickel and ammonia.
| 【1】 Chatterjee, S.; Ator, M.A.; Hudkins, R.L.; Bihovsky, R.; Dunn, D. (Cephalon, Inc.); Novel multicyclic cpds. and the use thereof. WO 0185686 . |
| 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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (II) | 60168 | 1H-indole-1-carboxylate | C9H6NO2 | 详情 | 详情 | |
| (III) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (IV) | 60169 | 1-(1H-indol-2-yl)cyclopentanol | C13H15NO | 详情 | 详情 | |
| (V) | 60170 | 2-(1-cyclopenten-1-yl)-1H-indole | C13H13N | 详情 | 详情 | |
| (VI) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (VII) | 60171 | 3a,3b,4,5,6,6a,7,11c-octahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione | C17H16N2O2 | 详情 | 详情 | |
| (VIII) | 60172 | 4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione | C17H12N2O2 | 详情 | 详情 | |
| (IX) | 60173 | 10-bromo-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione | C17H11BrN2O2 | 详情 | 详情 | |
| (X) | 60174 | 1,3-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-10-carbonitrile | C18H11N3O2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VII)Condensation of indole-6-carboxylic acid (VI) with cyclopentanone (VII) in the presence of aqueous NaOH and glycerol at 100 °C or KOH in aqueous MeOH at 75 °C yields the cyclopentene derivative (VIII), which is reduced to the corresponding cyclopentane (IX) by catalytic hydrogenation over Pd/C in THF or Pd(OH)2 in MeOH . Simultaneous esterification and N-methylation of the indole-carboxylic acid (IX) with CO(OMe)2 by means of K2CO3 in NMP at 130 °C , or sequential esterification with MeI and K2CO3 in DMF, followed by Nmethylation of the resultant indolyl-carboxylate with MeI using NaH in DMF , affords methyl 3-cyclopentyl-1-methylindole-6-carboxylate (X) . Bromination of intermediate (X) with Br2, optionally in the presence of NaOAc in acetonitrile or i-PrOAc, gives the 2-bromoindole derivative (XI) , which is then condensed with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) in the presence of Pd(OAc)2, TFP and Et3N in DME at 68 °C to provide boronate (XIIIa) . In an alternative procedure, transesterification of the methyl ester (X) with i-PrOLi in i-PrOH at 65 °C produces the more stable isopropyl ester (XIV), which is then brominated with Br2 in acetonitrile or i-PrOAc to afford the bromoindole derivative (XV). Condensation of bromide (XV) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) using Pd(TFP)2Cl2 or Pd(OAc)2, TFP and Et3N in acetonitrile at 82 °C yields boronate (XIIIb) . Finally, Suzuki coupling of pinacol boronates (XIIIa) or (XIIIb) with 5-bromo-2-iodopyrimidine (XVI) in the presence of K3PO4 at 76 °C, followed by ester hydrolysis of the resulting adducts (XVIIa) or (XVIIb) with NaOH in NMP, DMSO or i-PrOH , affords carboxylic acid (I) .
| 【1】 Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771. |
| 【2】 Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520. |
| 【3】 Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749. |
| 【4】 Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750. |
| 【5】 LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54. |
| 【6】 Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388. |
| 【7】 Khodabocus, A., Lu, Z.-H., Senanayake, C.H., Wei, H., Zhang, Y. (Boehringer Ingelheim Pharma GmbH & Co. KG). Process for preparing 2,3-disubstituted indoles. CN 103524495, EP 1853589, EP 2530082, JP 2008530117, KR 2014022796, US 2006183752, US 7642352, WO 2006086657. |
| 【8】 Fazal, G., Kukolj, G., Tsantrizos, Y.S. et al. (Boehringer Ingelheim (Canada) Ltd.). Viral polymerase inhibitors. CN 102424680, EP 1414797, EP 1891951, EP 2335700, JP 2004537564, JP 2009275037, US 2004024190, US 7141574, WO 2003010141. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIIa) | 67776 | methyl 3-cyclopentyl-1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate | C22H30BNO4 | 详情 | 详情 | |
| (XIIIb) | 67777 | isopropyl 3-cyclopentyl-1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate | C24H34BNO4 | 详情 | 详情 | |
| (XVIIa) | 67781 | methyl 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate | C20H20BrN3O2 | 详情 | 详情 | |
| (XVIIb) | 67780 | isopropyl 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate | C22H24BrN3O2 | 详情 | 详情 | |
| (I) | 67763 | 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid | C19H18BrN3O2 | 详情 | 详情 | |
| (VI) | 67771 | indole-6-carboxylic acid | 1670-82-2 | C9H7NO2 | 详情 | 详情 |
| (VII) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (VIII) | 67772 | 3-(cyclopent-1-en-1-yl)-1H-indole-6-carboxylic acid | C14H13NO2 | 详情 | 详情 | |
| (IX) | 67773 | 3-cyclopentyl-1H-indole-6-carboxylic acid | C14H15NO2 | 详情 | 详情 | |
| (X) | 67774 | methyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate | C16H19NO2 | 详情 | 详情 | |
| (XI) | 67775 | methyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate | C16H18BrNO2 | 详情 | 详情 | |
| (XII) | 55457 | 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane; Pinacolborane | 25015-63-8 | C6H13BO2 | 详情 | 详情 |
| (XIV) | 67778 | isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate | C18H23NO2 | 详情 | 详情 | |
| (XV) | 67779 | isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate | C18H22BrNO2 | 详情 | 详情 | |
| (XVI) | 67782 | 5-bromo-2-iodopyrimidine | 183438-24-6 | C4H2BrIN2 | 详情 | 详情 |