|
【结 构 式】 
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【分子编号】19273 【品名】acetyl chloride 【CA登记号】75-36-5 |
【 分 子 式 】C2H3ClO 【 分 子 量 】78.49792 【元素组成】C 30.6% H 3.85% Cl 45.16% O 20.38% |
合成路线1
该中间体在本合成路线中的序号：(II)By acetylation of 4-amino-N-[2-(diethylamino)ethyl]benzamide (I) with acethyl chloride (II) in chloroform.
| 【1】 Schreiber, E.C. (Bristol-Myers Squibb Co.); p-Acetamido-N-2-diethylaminoethylbenzamide and its salts. CA 977366; CH 520107; DE 2062978; FR 2081421; GB 1319980 . |
| 【2】 Roberts, P.J.; Castaner, J.; Acecainide hydrochloride. Drugs Fut 1978, 3, 9, 631. |
合成路线2
该中间体在本合成路线中的序号：(A)1) The acetylation of iminodibenzyl (I) with acetyl chloride (A) in refluxing toluene gives N-acetyl-iminodibenzyl (II), which by a Friedel-Kraft's reaction with methyl oxalyl chloride (B) and AlCl3 in CH2Cl2 or CS2 is converted to N-acetyl-3-(methyloxalyl)iminodibenzyl (III). The hydrolysis of (III) with NaOH in methanol-water yields N-acetyl-5-oxalyliminodibenzyl (IV), which by treatment with NaOH in water-ethanol at high temperature affords 3-oxalyliminodibenzyl (V). The reaction of (V) with hydroxylamine and acetic acid gives 3-hydroxylaminooxalyliminodibenzyl (VI), which by heating at 100 C in water is converted into 3-cyanoiminodibenzyl (VII). Finally, this compound is condensed with 3-(dimethylamino)propyl chloride (VIII) by means of NaH in DMF. 2) Compound (VII) can also be condensed with dimethylaminopropyl N,N-dimethylcarbamate (IX) by heating at 250 C. 3) The reaction of (VII) with phosgene gives N-chlorocarbonyl-3-cyanoiminodibenzyl (X), which is condensed with 3-dimethylaminopropanol (XI) to afford 3-cyanoiminodibenzyl-N-carboxylic acid 3-dimethylaminopropyl ester (XII). Finally, this compound is heated at 250 C under reduced pressure.
| 【1】 Dostert, P. (Hoffmann-La Roche, Inc.); 3-Cyano-N-(N,N-dimethylaminopropyl)-iminodibenzyl and salts thereof. US 4138482 . |
| 【2】 Blancafort, P.; Castaner, J.; Owen, R.T.; Serradell, M.N.; RO-11-2465. Drugs Fut 1981, 6, 1, 41. |
| 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) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (B) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (I) | 37165 | 10,11-dihydro-5H-dibenzo[b,f]azepine | 494-19-9 | C14H13N | 详情 | 详情 |
| (II) | 37166 | 1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-ethanone | C16H15NO | 详情 | 详情 | |
| (III) | 37167 | methyl 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetate | C19H17NO4 | 详情 | 详情 | |
| (IV) | 37168 | 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid | C18H15NO4 | 详情 | 详情 | |
| (V) | 37169 | 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid | C16H13NO3 | 详情 | 详情 | |
| (VI) | 37170 | 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-(hydroxyimino)acetic acid | C16H14N2O3 | 详情 | 详情 | |
| (VII) | 37171 | 10,11-dihydro-5H-dibenzo[b,f]azepine-3-carbonitrile | C15H12N2 | 详情 | 详情 | |
| (VIII) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (IX) | 37175 | 3-(dimethylamino)propyl dimethylcarbamate | C8H18N2O2 | 详情 | 详情 | |
| (X) | 37172 | 3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl chloride | C16H11ClN2O | 详情 | 详情 | |
| (XI) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (XII) | 37174 | 3-(dimethylamino)propyl 3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxylate | C21H23N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(C)The reaction of p-chlorobenzaldehyde (I) sodium cyanide and ethyl acetate gives ethyl 4-(p-chlorophenyl)-4-oxobutyrate (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reduction of (III) with Zn and aqueous HCl affords 4-(p-chlorophenyl)butyric acid (IV), which is condensed with heptylamine (B) by means of oxalyl chloride (A) in refluxing benzene to yield N-heptyl-4-(p-chlorophenyl)butyramide (V), which is reduced with diborane in refluxing THF to afford N-heptyl-4-(p-chlorophenyl)butylamine (VI). The acetylation of (VI) with acetyl chloride (C) by means of Na2CO3 in acetone gives N-acetyl-N-heptyl-4-(p-chlorophenyl)butylamine (VII), which is reduced with diborane as before to yield N-ethyl-N-heptyl-4-(p-chlorophenyl)butylamine (VIII). The quaternization of (VIII) with refluxing ethyl bromide (D) gives N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butylammonium bromide (IX), which by elution through a column with Dowex 1-X8, hydroxide form, resin is converted into N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butyl ammonium hydroxide (X). Finally, this compound is salified with diluted aqueous phosphoric acid.
| 【1】 Molloy, B.B.; Steinberg, M.I.; EP 0002604 . |
| 【2】 Hillier, K.; Castaner, J.; Clofilium Phosphate. Drugs Fut 1981, 6, 12, 764. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 23252 | 1-heptanamine; heptylamine | 111-68-2 | C7H17N | 详情 | 详情 |
| (A) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (D) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (I) | 29029 | 4-chlorobenzaldehyde | 104-88-1 | C7H5ClO | 详情 | 详情 |
| (II) | 37460 | ethyl 4-(4-chlorophenyl)-4-oxobutanoate | C12H13ClO3 | 详情 | 详情 | |
| (III) | 37461 | 4-(4-chlorophenyl)-4-oxobutyric acid | 3984-34-7 | C10H9ClO3 | 详情 | 详情 |
| (IV) | 37462 | 4-(4-chlorophenyl)butyric acid | C10H11ClO2 | 详情 | 详情 | |
| (V) | 37463 | 4-(4-chlorophenyl)-N-heptylbutanamide | C17H26ClNO | 详情 | 详情 | |
| (VI) | 37464 | N-[4-(4-chlorophenyl)butyl]-1-heptanamine; N-[4-(4-chlorophenyl)butyl]-N-heptylamine | C17H28ClN | 详情 | 详情 | |
| (VII) | 37465 | N-[4-(4-chlorophenyl)butyl]-N-heptylacetamide | C19H30ClNO | 详情 | 详情 | |
| (VIII) | 37466 | N-[4-(4-chlorophenyl)butyl]-N-ethyl-N-heptylamine; N-[4-(4-chlorophenyl)butyl]-N-ethyl-1-heptanamine | C19H32ClN | 详情 | 详情 | |
| (IX) | 37467 | N-[4-(4-chlorophenyl)butyl]-N,N-diethyl-1-heptanaminium bromide | C21H37BrClN | 详情 | 详情 | |
| (X) | 37468 | N-[4-(4-chlorophenyl)butyl]-N,N-diethyl-1-heptanaminium hydroxide | C21H38ClNO | 详情 | 详情 | |
| (C) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Trifluoromethylphenol (I) is converted into 2-hydroxy-4-trifluoromethylbenzoic acid (II) by treatment with potassium carbonate and carbon dioxide under pressure (Kolbe-Schmitt reaction). (II) is then converted with a suitable acetylating agent in the 2-acetoxy-4-trifluoromethylbenzoic acid (III).
| 【1】 Barra, E.F.; Marin, A.; 4-Trifluoromethylbenzoic acid derivatives as thromboembolic agents. DE 2641556; ES 459855; FR 2354335; GB 1588633; JP 52156831; US 4096252 . |
| 【2】 Marin, A.; Francia, E.; Garcia Rafanell, J.; Triflusal. Drugs Fut 1978, 3, 3, 225. |
合成路线5
该中间体在本合成路线中的序号：(C)The methylation of 2-amino-5-chlorobenzophenone (I) with dimethyl-sulfate affords the 5-chloro-2-methylaminobenzophenone (II), which is conden-sed with bromoacetyl bromide (A) to yieId 2-(2-bromo-N-methylacetamido)-5-chlorobenzophenone (III). The amonolysis of (III) with ammonia in methanol gives 2-(2-amino-N-methylacetamido)-5-chlorobenzophenone (IV), which is finally condensed with diketene (B) in refluxing acetone. This product can also be obtained by condensation of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (V) with acetyl chloride (C) and triethylamine in ether or with diketene (B) in acetone.
| 【1】 Szmuszkovicz, J.; et al.; Tetrahedron Lett 1971, 39, 39, 3665. |
| 【2】 Szmuszkovicz, J.; Oxazinobenzodiazepine derivatives. DE 1947226; ES 371392; FR 2018432; GB 1222294 . |
| 【3】 Szmuszkovicz, J.; Process for the preparation of 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d]benzodiazepine-4,7-6H-dione. CH 530414; JP 49025953B; NL 7014824; US 3575965 . |
| 【4】 Castaner, J.; Chatterjee, S.S.; Ketazolam. Drugs Fut 1976, 1, 6, 293. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (A) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (I) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (II) | 33972 | [5-chloro-2-(methylamino)phenyl](phenyl)methanone | 1022-13-5 | C14H12ClNO | 详情 | 详情 |
| (III) | 33973 | N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-methylacetamide | C16H13BrClNO2 | 详情 | 详情 | |
| (IV) | 33974 | 2-amino-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide | C16H15ClN2O2 | 详情 | 详情 | |
| (V) | 33975 | 7-chloro-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one | C16H15ClN2O | 详情 | 详情 | |
| (C) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The Friedel-Crafts condensation of 2-hydroxybenzoic acid methyl ester (I) with 13C-labeled acetyl chloride (II) by means of AlCl3 in dichloromethane gives 5-acetyl-2-hydroxybenzoic acid methyl ester (III), which is brominated with Br2 in CHCl3 yielding the bromoacetyl compound (IV). The condensation of (IV) with the secondary amine (V) by means of DIEA in THF affords the tertiary amine (VI), which is reduced with LiAlD4 in refluxing ethyl ether to provide the trideuterated triol (VII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Goodwin, T.E.; et al.; Synthesis of 13C,2H3-salmeterol: An analytical internal standard for pharmacokinetic studies. J Label Compd Radiopharm 2000, 43, 1, 65. |
| 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) | 15754 | methyl salicylate | 119-36-8 | C8H8O3 | 详情 | 详情 |
| (II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (II) | 44648 | acetyl chloride | 1520-57-6 | C2H3ClO | 详情 | 详情 |
| (III) | 30753 | methyl 5-acetyl-2-hydroxybenzoate | 16475-90-4 | C10H10O4 | 详情 | 详情 |
| (III) | 44649 | methyl 5-acetyl-2-hydroxybenzoate | C10H10O4 | 详情 | 详情 | |
| (IV) | 35836 | methyl 5-(2-bromoacetyl)-2-hydroxybenzoate | C10H9BrO4 | 详情 | 详情 | |
| (IV) | 44650 | methyl 5-(2-bromoacetyl)-2-hydroxybenzoate | C10H9BrO4 | 详情 | 详情 | |
| (V) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (VI) | 35838 | methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate | C33H41NO5 | 详情 | 详情 | |
| (VI) | 44651 | methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate | C33H41NO5 | 详情 | 详情 | |
| (VII) | 35839 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 | |
| (VII) | 44652 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：The bromination of 3,4-dihydro-1H-2-benzopyran (VII) with Br2 gives the 1-bromo derivative (VIII), which, without isolation, is treated with hot HBr yielding 2-(2-bromoethyl)benzaldehyde (IX). The condensation of (IX) with nitromethane in acidic medium affords the nitrostyrene (X), which is cyclized with treatment with FeCl3 and acetyl chloride giving 4-(2-bromoethyl)-3-chloroindolin-2-one (XI). The dechlorination of (XI) with NaH2PO2 over Pd/C yields 4-(2-bromoethyl)indolin-2-one (XII), which is finally condensed with dipropylamine (II).
| 【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (VII) | 34866 | 3,4-dihydro-1H-isochromene | 493-05-0 | C9H10O | 详情 | 详情 |
| (VIII) | 34867 | 1-bromo-3,4-dihydro-1H-isochromene | C9H9BrO | 详情 | 详情 | |
| (IX) | 34868 | 2-(2-bromoethyl)benzaldehyde | C9H9BrO | 详情 | 详情 | |
| (X) | 34869 | 1-(2-bromoethyl)-2-[(E)-2-nitroethenyl]benzene | C10H10BrNO2 | 详情 | 详情 | |
| (XI) | 34870 | 4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indol-2-one | C10H9BrClNO | 详情 | 详情 | |
| (XII) | 34871 | 4-(2-bromoethyl)-1,3-dihydro-2H-indol-2-one | C10H10BrNO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：The reaction of 3,4-dihydro-1H-2-benzopyran (VII) with benzoyl chloride and ZnCl2 gives benzoic acid 2-[2-(chloromethyl)phenyl]ethyl ester (XIII), which is condensed with hexamethylenetetramine (XIV) yielding the amminium salt (XV). The hydrolysis of (XV) affords 2-(2-benzoyloxyethyl) benzaldehyde (XVI), which is condensed with nitromethane as before to give the nitrostyrene (XVII). The cyclization of (XVII) with FeCl3 and acetyl chloride as before yields 4-(2-benzoyloxyethyl)-3-chloroindolin-2-one (XVIII), which is dechlorinated with hydrazine and Pd/C to the indolinone (XIX). The hydrolysis of (XIX) with NaOH affords 4-(2-hydroxyethyl)indolin-2-one (XX), which is acylated with TsCl giving the tosylate (XXI). Finally, this compound is condensed with dipropylamine (II).
| 【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (VII) | 34866 | 3,4-dihydro-1H-isochromene | 493-05-0 | C9H10O | 详情 | 详情 |
| (XIII) | 34872 | 2-(chloromethyl)phenethyl benzoate | C16H15ClO2 | 详情 | 详情 | |
| (XIV) | 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 |
| (XV) | 34874 | 1-[2-[2-(benzoyloxy)ethyl]benzyl]-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane chloride | C22H27ClN4O2 | 详情 | 详情 | |
| (XVI) | 34875 | 2-formylphenethyl benzoate | C16H14O3 | 详情 | 详情 | |
| (XVII) | 34876 | 2-[(E)-2-nitroethenyl]phenethyl benzoate | C17H15NO4 | 详情 | 详情 | |
| (XVIII) | 34877 | 2-(3-chloro-2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H14ClNO3 | 详情 | 详情 | |
| (XIX) | 34878 | 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H15NO3 | 详情 | 详情 | |
| (XX) | 34879 | 4-(2-Hydroxyethyl)indolin-2-one | 139122-19-3 | C10H11NO2 | 详情 | 详情 |
| (XXI) | 34880 | 4-heptanol | 589-55-9 | C7H16O | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(A)The acetylation of 4-hydroxymethyl-1,3-dioxolane (XII) gives the corresponding acetate (XIII), which by reaction with acetic anhydride and ZnCl2 is converted to 1,3-diacetoxy-2-(acetoxymethoxy)propane (XIV). The condensation of (XIV) with diacetylguanine (VI) by means of ethanesulfonic acid (B) yields the triacetoxy precursor (XV), which is hydrolyzed with aqueous methylamine.
| 【1】 Field, A.K.; Tolman, R.L.; Ashton, W.A.; Karkas, J.D.; Activation by thymidine kinase and potent antiherpetic activity of 2'-nor-2'-deoxyguanosine (2'NDG). Biochem Biophys Res Commun 1982, 108, 4, 1716. |
| 【2】 Galloway, K.S.; Radatus, B.K.; Kennell, W.L.; Smith, K.O.; Ogilvie, K.K.; A new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 1982, 22, 1, 55-61. |
| 【3】 Pento, J.T.; Serradell, M.N.; Castaner, J.; BIOLF-62. Drugs Fut 1985, 10, 5, 365. |
| 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) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (B) | 29169 | 1-ethanesulfonic acid | 594-45-6 | C2H6O3S | 详情 | 详情 |
| (VI) | 29161 | N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine | 3056-33-5 | C9H9N5O3 | 详情 | 详情 |
| (XII) | 29166 | 1,3-dioxolan-4-ylmethanol | 4740-78-7 | C4H8O3 | 详情 | 详情 |
| (XIII) | 29167 | 1,3-dioxolan-4-ylmethyl acetate | C6H10O4 | 详情 | 详情 | |
| (XIV) | 29168 | 3-(acetoxy)-2-[(acetoxy)methoxy]propyl acetate | C10H16O7 | 详情 | 详情 | |
| (XV) | 29170 | 2-[[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(acetoxy)propyl acetate | C15H19N5O7 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XV)The intermediate tricyclic carbaldehyde has been obtained by two different methods: 1. The dicarboxylic ester (I) is methylated with Me-I and Ag2O in dioxane to give the dimethoxy compound (II), which is reduced with LiAlH4 in THF to obtain the dicarbinol (III). Monoesterification of (III) with benzoyl chloride and pyridine in dichloromethane yields the monobenzoate (IV), which is oxidized with DMP to afford the carbaldehyde (V). The Grignard reaction of (V) with methylmagnesium bromide and MeLi in THF provides the diol (VI), which is oxidized with oxalyl chloride to furnish the desired intermediate carbaldehyde (VII). 2. The reaction of the tricyclic ketone (VIII) with phosphonium bromide (IX) by means of tBu-OK in THF gives methylene derivative (X), which by hydroboration with BH3 and H2O2 in THF yields the carbinol (XI). The oxidation of (XI) with DPP affords the carbaldehyde (XII), which is condensed with the 1-aminopyrrolidine (XIII) to afford the hydrazone (XIV). The acylation of (XIV) with acetyl chloride and LDA in THF provides the acetyl derivative (XV), which is finally treated with oxalic acid go give the desired intermediate carbaldehyde (VII).
| 【1】 Kita, Y.; et al.; Total synthesis of the antitumor antribiotic (±)-fredericamycin A by a linear approach. Chemistry (Weinheim) 2000, 6, 21, 3897. |
| 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) | 48755 | dimethyl 9-hydroxy-3-methyl-1-oxo-1,2,6,7-tetrahydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate | C17H17NO6 | 详情 | 详情 | |
| (II) | 48756 | dimethyl 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate | C19H21NO6 | 详情 | 详情 | |
| (III) | 48757 | [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methanol | C17H21NO4 | 详情 | 详情 | |
| (IV) | 48758 | [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methyl benzoate | C24H25NO5 | 详情 | 详情 | |
| (V) | 48759 | (8-formyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methyl benzoate | C24H23NO5 | 详情 | 详情 | |
| (VI) | 48760 | 1-[8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanol | C18H23NO4 | 详情 | 详情 | |
| (VII) | 48761 | 8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C18H19NO4 | 详情 | 详情 | |
| (VIII) | 48762 | 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinolin-8-one | C15H15NO3 | 详情 | 详情 | |
| (IX) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (X) | 48763 | 1,9-dimethoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinoline; 1-methoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinolin-9-yl methyl ether | C16H17NO2 | 详情 | 详情 | |
| (XI) | 48764 | (1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methanol | C16H19NO3 | 详情 | 详情 | |
| (XII) | 46913 | (2R)-2-(methoxymethyl)pyrrolidinylamine; (2R)-2-(methoxymethyl)-1-pyrrolidinamine | 59983-39-0 | C6H14N2O | 详情 | 详情 |
| (XIII) | 48765 | 1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C16H17NO3 | 详情 | 详情 | |
| (XIV) | 48766 | N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-N-[(2R)-2-(methoxymethyl)pyrrolidinyl]amine; (2R)-N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-2-(methoxymethyl)-1-pyrrolidinamine | C22H29N3O3 | 详情 | 详情 | |
| (XV) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (XVI) | 48767 | 1-[1,9-dimethoxy-8-([[(2R)-2-(methoxymethyl)pyrrolidinyl]imino]methyl)-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanone | C24H31N3O4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)The syntheses of remacemide [13C]-, [14C]-, [2H]-,and [3H]-labeled in several different positions have been described: The Friedel Crafts condensation of benzene with acetyl chloride (II) by means of AlCl3 in CS2 gives acetophenone (III), which by a Grignard condensation with benzylmagnesium chloride (IV) in THF yields 1,2-diphenyl-3-propanol (V). Reaction of (V) with NaCN and sulfuric acid in acetic acid affords the formamide (VI), which is hydrolyzed with refluxing aqueous HCl to give the amine (VII). The condensation of (VII) with N-Boc-glycine (VIII) and DCC or with the N-Boc-glycine mixed anhydride (IX) and TEA in dichloromethane yields the protected glycinamide (X), which is finally deprotected with HCl in refluxing methanol. Alternatively, condensation of amine (VII) with chloroacetyl chloride (XI) by means of pyridine in dichloromethane provides the chloroacetamide (XII), which is finally treated with ammonia in ethanol/dichloromethane. In this reaction sequence, the use of [carbonyl-14C]-acetophenone (III), [13C6]-benzene (I), [13C2]-acetyl chloride (II), the [1-13C]-glycines (VIII) and (IX) or the [2-3H]-glycine (VIII) as starting materials affords remacemide labeled in the corresponding positions. [2H or 3H]-remacemide labeled in 2,6-positions of the 1-phenyl ring is obtained by submitting the amine (VII) to isotopic exchange with 2H2O/RhCl3, 2H2/Iridium complex, or 3H2/Iridium complex.
| 【1】 Dawson, G.E.; Coombs, M.E.; Fedorchuk, M.; et al.; Preparation of remacemide hydrochloride labelled with carbon-14, carbon-13, deuterium and tritium. J Label Compd Radiopharm 2000, 43, 6, 533. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (III) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (IV) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (V) | 41763 | 1,2-diphenyl-2-propanol | 5342-87-0 | C15H16O | 详情 | 详情 |
| (VI) | 41764 | 1-methyl-1,2-diphenylethylformamide | C16H17NO | 详情 | 详情 | |
| (VII) | 41765 | 1-methyl-1,2-diphenylethylamine; 1,2-diphenyl-2-propanamine | C15H17N | 详情 | 详情 | |
| (VIII) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (IX) | 41766 | [(tert-butoxycarbonyl)amino]acetic 1,1-dimethylpropionic anhydride | C12H21NO5 | 详情 | 详情 | |
| (X) | 41767 | tert-butyl 2-[(1-methyl-1,2-diphenylethyl)amino]-2-oxoethylcarbamate | C22H28N2O3 | 详情 | 详情 | |
| (XI) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XII) | 41768 | 2-chloro-N-(1-methyl-1,2-diphenylethyl)acetamide | C17H18ClNO | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)The synthesis of atorvastatin [14C]-labeled on the side chain has been described: The reaction of [14C]-labeled sodium acetate (I) with phthaloyl chloride (II) in refluxing xylene gives the acyl chloride (III), which is treated with 1,2,2-triphenyl-1(S),2-ethanediol (IV) in dichloromethane yielding the expected monoacetate (V). The condensation of (V) with the pyrrolepropionaldehyde (VI) by means of lithium diisopropylamide (LDA) in THF affords the chiral beta-hydroxyester (VII), which is transesterified with sodium methoxide in methanol providing the corresponding methyl ester (VIII). The condensation of (VIII) with tert-butyl acetate (IX) by means of LDA in THF gives the beta-oxo-delta-hydroxyester (X), which is regioselectively reduced to the dihydroxyester (XI) by means of BEt3, NaBH4 and H2O2 in THF. The hydrolysis of (XI) with NaOH in THF/water, followed by acidification yields the free acid (XII), which is heated in refluxing toluene in a Dean-Stark trap to provide lactone (XIII). The reaction of (XIII) with NaOH in THF/methanol gives the corresponding sodium salt (XIV), which is finally treated with CaCl2 in the same solvent.
| 【1】 Woo, P.W.K.; Lee, H.T.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid-regulating agent. Part II. Synthesis of side-chain-labeled [C-14] atorvastatin. J Label Compd Radiopharm 1999, 42, 2, 129. |
| 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) | 27912 | Sodium acetate | 127-09-3 | C2H3NaO2 | 详情 | 详情 |
| (I) | 45240 | sodium acetate | C2H3NaO2 | 详情 | 详情 | |
| (II) | 23811 | phthaloyl dichloride;1,2-Benzenedicarbonyl dichloride;o-Phthaloyl chloride | 88-95-9 | C8H4Cl2O2 | 详情 | 详情 |
| (III) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (III) | 45241 | acetyl chloride | C2H3ClO | 详情 | 详情 | |
| (IV) | 27913 | (2S)-1,1,2-triphenyl-1,2-ethanediol | 95061-46-4 | C20H18O2 | 详情 | 详情 |
| (V) | 11540 | (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate | 95061-47-5 | C22H20O3 | 详情 | 详情 |
| (V) | 45242 | (1S)-2-hydroxy-1,2,2-triphenylethyl acetate | C22H20O3 | 详情 | 详情 | |
| (VI) | 15386 | 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide | C29H27FN2O2 | 详情 | 详情 | |
| (VII) | 15395 | (1S)-2-hydroxy-1,2,2-triphenylethyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate | 134394-96-0 | C51H47FN2O5 | 详情 | 详情 |
| (VII) | 45243 | (1S)-2-hydroxy-1,2,2-triphenylethyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate | C51H47FN2O5 | 详情 | 详情 | |
| (VIII) | 15396 | methyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate | C32H33FN2O4 | 详情 | 详情 | |
| (VIII) | 45244 | methyl (3R)-5-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3-hydroxypentanoate | C32H33FN2O4 | 详情 | 详情 | |
| (IX) | 15397 | tert-butyl acetate | 540-88-5 | C6H12O2 | 详情 | 详情 |
| (X) | 15398 | tert-butyl (5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate | C37H41FN2O5 | 详情 | 详情 | |
| (X) | 45245 | tert-butyl (5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate | C37H41FN2O5 | 详情 | 详情 | |
| (XI) | 27914 | tert-butyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C37H43FN2O5 | 详情 | 详情 | |
| (XI) | 45246 | tert-butyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C37H43FN2O5 | 详情 | 详情 | |
| (XII) | 15390 | (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid | C33H35FN2O5 | 详情 | 详情 | |
| (XII) | 45247 | (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid | C33H35FN2O5 | 详情 | 详情 | |
| (XIII) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 | |
| (XIII) | 45248 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 | |
| (XIV) | 27911 | sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C33H34FN2NaO5 | 详情 | 详情 | |
| (XIV) | 45249 | sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C33H34FN2NaO5 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2OCHCl3) under Schotten-Baumann conditions.
| 【1】 Silvestre, J.S.; Bayes, M.; Chilman-Blair, K.; Castaner, J.; Agomelatine. Drugs Fut 2003, 28, 1, 7. |
| 【2】 Andrieux, J.; Houssin, R.; Said, Y.; Guardiola-Lemaitre, B.; Lesieur, D. (ADIR et Cie.); Novel derivs. with a naphthalenic structure, their process of preparation and pharmaceutical compsns. containing them. EP 0447285; FR 2658819; JP 1995048331; US 5318994 . |
| 【3】 Guardiola-Lemaitre, B.; Renard, P.; Pfeiffer, B.; Caignard, D.-H.; Andrieux, J.; Howell, H.-E.; Morgan, P.; Yous, S.; Lesieur, D.; Adam, G.; Novel naphthalenic ligands for the melatonin receptor. J Pharm Belg 1992, 47, 4, 374. |
| 【4】 Morgan, P.J.; Howell, H.E.; Lesieur, D.; Guardiola-Lemaitre, B.; Pfeiffer, B.; Andrieux, J.; Renard, P.; Yous, S.; Novel naphthalenic ligands with high affinity for the melatonin receptor. J Med Chem 1992, 35, 8, 1484. |
| 【5】 Depreux, P.; Lesieur, D.; Mansour, H.A.; et al.; Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J Med Chem 1994, 37, 20, 3231. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 58079 | ethyl 2-[7-methoxy-3,4-dihydro-1(2H)-naphthalenylidene]acetate | C15H18O3 | 详情 | 详情 | |
| (III) | 58080 | ethyl 2-(7-methoxy-1-naphthyl)acetate | C15H16O3 | 详情 | 详情 | |
| (IV) | 58081 | 2-(7-methoxy-1-naphthyl)acetic acid | C13H12O3 | 详情 | 详情 | |
| (V) | 58082 | 2-(7-methoxy-1-naphthyl)acetamide | C13H13NO2 | 详情 | 详情 | |
| (VI) | 58083 | 2-(7-methoxy-1-naphthyl)-1-ethanamine; 2-(7-methoxy-1-naphthyl)ethylamine | C13H15NO | 详情 | 详情 | |
| (VII) | 36604 | 2-(7-methoxy-1-naphthyl)acetonitrile | C13H11NO | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XXI)7) The Friedel-Crafts condensation of thioanisole (XX) with acetyl chloride (XXI) by means of AlCl3 in dichlorobenzene gives the corresponding acetophenone (X), which is oxidized with H2O2/WO4Na2 to the ketosulfone (XI). The bromination of (XI) with Br2 in acetic acid/48% HBr affords the phenacyl bromide (XII), which is condensed with phenylacetic acid sodium salt (XXIII) in DMF, giving the phenacyl ester (XXII). Finally, this compound is cyclized by means of diisopropylamine in DMF.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Rofecoxib. Drugs Fut 1998, 23, 12, 1287. |
| 【2】 Frey, L.F.; Dolling, U.H.; Desmond, R.; Tillyer, R.D.; Tschaen, D.M. (Merck & Co., Inc.); Process of preparing phenyl heterocycles useful as COX-2 inhibitors. WO 9800416 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 19262 | 1-[4-(methylsulfanyl)phenyl]-1-ethanone；4'-Methylthioacetophenon；4’-(methylthio)acetophenone | 1778-09-2 | C9H10OS | 详情 | 详情 |
| (XI) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (XII) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 | |
| (XX) | 19272 | methyl phenyl sulfide; 1-(methylsulfanyl)benzene | 100-68-5 | C7H8S | 详情 | 详情 |
| (XXI) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (XXII) | 19274 | 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl 2-phenylacetate | C17H16O5S | 详情 | 详情 | |
| (XXIII) | 19275 | sodium 2-phenylacetate | 114-70-5 | C8H7NaO2 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(II)The Friedel Crafts acylation of thioanisole (I) with acetyl chloride (II) and AlCl3 in chloroform gives 4-(methylsulfanyl)acetophenone (III), which is oxidized with monoperoxyphthalic acid (MMPP) in methanol/dichloromethane to yield 4-(methylsulfonyl)acetophenone (IV). The bromination of (IV) with Br2 and AlCl3 in chloroform affords 4-(methylsulfonyl)phenacyl bromide (V), which is finally cyclized by means of DBU and TEA in acetonitrile to provide the target furanone derivative.
| 【1】 Thérien, M.; Gauthier, J.Y.; Leblanc, Y.; Leger, S.; Perrier, H.; Prasit, P.; Wang, Z.; Synthesis of rofecoxib, (MK 0966, Vioxx(R)) 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone), a selective and orally active inhibitor of cyclooxygenase-2. Synthesis (Stuttgart) 2001, 12, 1778. |
| 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) | 19272 | methyl phenyl sulfide; 1-(methylsulfanyl)benzene | 100-68-5 | C7H8S | 详情 | 详情 |
| (II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (III) | 19262 | 1-[4-(methylsulfanyl)phenyl]-1-ethanone；4'-Methylthioacetophenon；4’-(methylthio)acetophenone | 1778-09-2 | C9H10OS | 详情 | 详情 |
| (IV) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (V) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 | |
| (VI) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：In an alternative procedure, 3-methoxy-2-nitrobenzoic acid (II) was treated with SOCl2 in the presence of DMF in THF, and the resulting acid chloride (III) was converted to amide (IV) with aqueous ammonia. Catalytic hydrogenation of (IV) over Pd/C produced aniline (V), which was then acetylated with AcCl and pyridine. The crude acetylamino compound (VI) was cyclized by treatment with aqueous NaOH to yield the quinazolinone (VII). Finally, demethylation of the methoxy group of (VII) with BBr3 provided the required 8-hydroxyquinazolinone.
| 【1】 Griffin, R.J.; Srinivasan, S.; Bowman, K.; Calvert, A.H.; Curtin, N.J.; Newell, D.R.; Pemberton, L.C.; Golding, B.T.; Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). J Med Chem 1998, 41, 26, 5247. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (II) | 25827 | 3-methoxy-2-nitrobenzoic acid | 4920-80-3 | C8H7NO5 | 详情 | 详情 |
| (III) | 25828 | 3-methoxy-2-nitrobenzoyl chloride | C8H6ClNO4 | 详情 | 详情 | |
| (IV) | 25829 | 3-methoxy-2-nitrobenzamide | C8H8N2O4 | 详情 | 详情 | |
| (V) | 25830 | 2-amino-3-methoxybenzamide | C8H10N2O2 | 详情 | 详情 | |
| (VI) | 25831 | 2-(acetamido)-3-methoxybenzamide | C10H12N2O3 | 详情 | 详情 | |
| (VII) | 25832 | 8-methoxy-2-methyl-4(3H)-quinazolinone | C10H10N2O2 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：Thiol (II) was prepared by reduction of 4-ethylbenzenesulfonyl chloride (I) with LiAlH4. Subsequent alkylation of (II) with ethyl 4-chloroacetoacetate (III) provided sulfide (IV), which was cyclized to the required benzothiophene (V) on heating with polyphosphoric acid in toluene. Basic hydrolysis of the ester group of (V) gave carboxylic acid (IV). After conversion of (VI) to the corresponding acid chloride with SOCl2, treatment with NH4OH yielded amide (VII). This was dehydrated to nitrile (VIII) using trifluoroacetic anhydride and triethylamine. Reduction of the nitrile function of (VIII) by means of LiAlH4 and AlCl3 gave rise to the corresponding primary amine, which was isolated as the hydrochloride salt (IX). Finally, acylation with acetyl chloride furnished the title acetamide.
| 【1】 Lesieur, D.; Fourmaintraux, E.; Depreux, P.; Delagrange, P.; Renard, P.; Guardiola-Lemaître, B. (ADIR et Cie.); Alkyl(hetero)cyclic cpds., process for their preparation and pharmaceutical compsns. containing them. CA 2167039; CA 2167040; EP 0721938; EP 0721947; FR 2729147; JP 1996231530; JP 1996239353; US 5693665; US 5703121; US 5780512 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 26619 | 4-ethylbenzenesulfonyl chloride | 16712-69-9 | C8H9ClO2S | 详情 | 详情 |
| (II) | 32934 | 4-ethylbenzenethiol; 4-ethylphenylhydrosulfide | 4946-13-8 | C8H10S | 详情 | 详情 |
| (III) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (IV) | 32935 | ethyl 4-[(4-ethylphenyl)sulfanyl]-3-oxobutanoate | C14H18O3S | 详情 | 详情 | |
| (V) | 32936 | ethyl 2-(5-ethyl-1-benzothiophen-3-yl)acetate | C14H16O2S | 详情 | 详情 | |
| (VI) | 32937 | 2-(5-ethyl-1-benzothiophen-3-yl)acetic acid | C12H12O2S | 详情 | 详情 | |
| (VII) | 32938 | 2-(5-ethyl-1-benzothiophen-3-yl)acetamide | C12H13NOS | 详情 | 详情 | |
| (VIII) | 32939 | 2-(5-ethyl-1-benzothiophen-3-yl)acetonitrile | C12H11NS | 详情 | 详情 | |
| (IX) | 32940 | 2-(5-ethyl-1-benzothiophen-3-yl)ethylamine; 2-(5-ethyl-1-benzothiophen-3-yl)-1-ethanamine | C12H15NS | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：3-Mercapto-3-methylbutyric acid (I) was protected as the tetrahydropyranyl derivative (III) using dihydropyran (II) and HCl. Subsequent treatment of (III) with triphosgene and triethylamine generated the acid anhydride (IV). Condensation of yohimbine (V) with anhydride (IV) in the presence of dimethylaminopyridine provided ester (VI). Further acetylation of (VI) with acetyl chloride in acetic acid gave rise to the N,S-diacetyl compound (VII), which was selectively deacetylated with mercuric trifluoroacetate, yielding thiol (VIII). Finally, reaction of (VIII) with NaNO2 and HCl furnished the corresponding S-nitrosyl derivative.
| 【1】 Saenz de Tejada, I.; Schroeder, J.D.; Carvey, D.S. (NitroMed Inc.); Nitrosated and nitrosylated alpha-adrenergic receptor antagonist cpds., compsns. and their uses. JP 2000505424; WO 9727749 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 32947 | 3-methyl-3-sulfanylbutyric acid | C5H10O2S | 详情 | 详情 | |
| (II) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (III) | 32948 | 3-methyl-3-(tetrahydro-2H-pyran-2-ylsulfanyl)butyric acid | C10H18O3S | 详情 | 详情 | |
| (IV) | 32949 | 2-methyl-2-(tetrahydro-2H-pyran-2-ylsulfanyl)butyric anhydride | C20H34O5S2 | 详情 | 详情 | |
| (V) | 32950 | methyl (1R,2S,4aR,13bS,14aS)-2-hydroxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate | 146-48-5 | C21H26N2O3 | 详情 | 详情 |
| (VI) | 32951 | methyl (1R,2S,4aR,13bS,14aS)-2-[[3-methyl-3-(tetrahydro-2H-pyran-2-ylsulfanyl)butanoyl]oxy]-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate | C31H42N2O5S | 详情 | 详情 | |
| (VII) | 32952 | methyl (1R,2S,4aR,13bS,14aS)-13-acetyl-2-[[3-(acetylsulfanyl)-3-methylbutanoyl]oxy]-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate | C30H38N2O6S | 详情 | 详情 | |
| (VIII) | 32953 | methyl (1R,2S,4aR,13bS,14aS)-13-acetyl-2-[(3-methyl-3-sulfanylbutanoyl)oxy]-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate | C28H36N2O5S | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(V)The intermediate amino pyrazole (I) was prepared as follows. Acylation of malononitrile (IV) with acetyl chloride (V) in the presence of Et3N afforded (1-hydroxyethyliden)malononitrile (VI). Subsequent methylation of the hydroxyl group with dimethyl sulfate gave enol ether (VII). Alternatively, malononitrile (IV) was converted to the ethyl enol ether (VIII) by condensation with triethyl orthoacetate in the presence of Ac2O. Cyclization of either (VII) or (VIII) with phenylhydrazine (IX) furnished 5-amino-4-cyano-1-phenylpyrazole (I).
| 【1】 Hasegawa, H.; et al.; Synthesis of endothelin converting enzyme inhibitors and their structure activity relationships. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 1P-21. |
| 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) | 49117 | 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile | C11H10N4 | 详情 | 详情 | |
| (IV) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (IV) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (V) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (VI) | 56569 | 2-(1-hydroxyethylidene)malononitrile | C5H4N2O | 详情 | 详情 | |
| (VII) | 56570 | 2-(1-methoxyethylidene)malononitrile | C6H6N2O | 详情 | 详情 | |
| (VIII) | 56571 | 2-(1-ethoxyethylidene)malononitrile | C7H8N2O | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：The condensation of 2-fluoronitrobenzene (I) with acetone oxime (II) by means of NaH in DMF gives acetone O-(2-nitrophenyl)oxime (III), which is cyclized to 2-methyl-7-nitrobenzofuran (IV) by means of H2SO4. The Friedel Crafts acylation of (IV) with acetyl chloride and AlCl3 in dichloromethane affords 3-acetyl-2-methyl-7-nitrobenzofuran (V), which is reduced to the corresponding amino derivative (VI) with Fe and HCl in ethanol. The condensation of (VI) with 2,6-dichlorobenzoyl chloride (VII) by means of triethylamine in dichloroethane yields N-(3-acetyl-2-methylbenzofuran-7-yl)-2,6-dichlorobenzamide (VIII), which is finally submitted to a Grignard reaction with methylmagnesium bromide in THF.
| 【1】 Yamazaki, H.; et al.; Synthesis and pharmacological activities of novel benzofuran derivatives as vacuolar type H+-ATPase inhibitors. Symp Med Chem 1998, Abst 2-P-32. |
| 【2】 Kawai, Y.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K.; Yatabe, T.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Benzofuran derivs. useful as inhibitors of bone resorption. EP 0757682; JP 1997512795; US 5858995; WO 9529907 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 17791 | acetone oxime; Acetoxime | 127-06-0 | C3H7NO | 详情 | 详情 |
| (III) | 25083 | acetone O-(2-nitrophenyl)oxime | C9H10N2O3 | 详情 | 详情 | |
| (IV) | 25084 | 2-methyl-7-nitro-1-benzofuran | C9H7NO3 | 详情 | 详情 | |
| (V) | 25086 | 1-(7-amino-2-methyl-1-benzofuran-3-yl)-1-ethanone | C11H11NO2 | 详情 | 详情 | |
| (VI) | 24086 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate | C25H25N3O6S | 详情 | 详情 | |
| (VII) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (VIII) | 25088 | N-(3-acetyl-2-methyl-1-benzofuran-7-yl)-2,6-dichlorobenzamide | C18H13Cl2NO3 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：Condensation of 4-chloroacetophenone (I) with ethyl diethoxyacetate (II) in the presence of lithium hexamethyldisilazide afforded diketoacetal (III). Formation of pyrazole (V) was accomplished by treatment of (III) with 4-methoxy-phenylhydrazine (IV). Subsequent acid hydrolysis of the diethyl acetal gave aldehyde (VI), which was condensed with carbon tetrabromide using triphenyl phosphine to furnish dibromoethylene compound (VII). Elimination of HBr in (VII) by treatment with tetrabutylammonium fluoride produced bromoacetylene (VIII). After lithium-bromine exchange, addition of acetaldehyde yielded the propargyl alcohol (IX). Further Mitsunobu coupling of (IX) with N,O-bis(tert-butoxycarbonyl)hydroxylamine (X) gave the N,O-bis-protected N-alkyl hydroxylamine (XI). After Boc deprotection of (XI) by means of trifluoroacetic acid, coupling with acetyl chloride provided the O-acetyl hydroxamic acid (XII). Finally, cleavage of the O-acyl group of (XII) with methanolic NaOH furnished the title compound.
| 【1】 Wetter, S.K.; Connolly, P.J.; Beers, K.N.; et al.; N-Hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase. Bioorg Med Chem Lett 1999, 9, 7, 979. |
| 【2】 Chen, R.; Wachter, M.; Connolly, P. (Ortho-McNeil Pharmaceutical, Inc.); Acetylenic 1,5-diarylpyrazoles as antiinflammatory agents. US 5925769 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (II) | 25674 | ethyl 2,2-diethoxyacetate | 6065-82-3 | C8H16O4 | 详情 | 详情 |
| (III) | 34716 | 1-(4-chlorophenyl)-4,4-diethoxy-1,3-butanedione | C14H17ClO4 | 详情 | 详情 | |
| (IV) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (V) | 34717 | 4-[5-(4-chlorophenyl)-3-(diethoxymethyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(diethoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole | C21H23ClN2O3 | 详情 | 详情 | |
| (VI) | 34718 | 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde | C17H13ClN2O2 | 详情 | 详情 | |
| (VII) | 34719 | 4-[5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1-(4-methoxyphenyl)-1H-pyrazole | C18H13Br2ClN2O | 详情 | 详情 | |
| (VIII) | 34720 | 3-(2-bromoethynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole; 4-[3-(2-bromoethynyl)-5-(4-chlorophenyl)-1H-pyrazol-1-yl]phenyl methyl ether | C18H12BrClN2O | 详情 | 详情 | |
| (IX) | 34721 | 4-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-3-butyn-2-ol | C20H17ClN2O2 | 详情 | 详情 | |
| (X) | 34722 | 2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane | C10H19NO5 | 详情 | 详情 | |
| (XI) | 34723 | 3-(3-[(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino]-1-butynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole | C30H34ClN3O6 | 详情 | 详情 | |
| (XII) | 34724 | 1-((acetoxy)[3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-1-methyl-2-propynyl]amino)-1-ethanone | C24H22ClN3O4 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：The cyclization of benzophenone (I) with hydrazine in isopropanol gives 8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (II), which is treated with KCN in AcOH at 70 C in a sealed tube to afford nitrile (III). Subsequent treatment of (III) with acetyl chloride gave the N-acetyl benzodiazepine (IV). Finally, the nitro group of (IV) was reduced to the target amine by transfer hydrogenation using hydrazine and Pd/C.
| 【1】 Andrási, F.; Balogh, T.; Botka, P.; Elekes, I.; Goldschmidt, K.; Hámori, T.; Korosi, J.; Láng, T.; Moravcsik, I.; Sineger, E.; Somogyi, G.; Zolyomi, G. (Egis Pharmaceuticals Ltd.); 5H-2,3-Benzodiazepine derivs., process for their preparation and pharmaceutical compsns. which contain them. FR 2566774; HU 191702 . |
| 【2】 8-Substd.-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine derivs., as AMPA/kainate receptor inhibitors. EP 1003749; WO 9907707 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 35397 | 1-[6-(4-nitrobenzoyl)-1,3-benzodioxol-5-yl]acetone | C17H13NO6 | 详情 | 详情 | |
| (II) | 29266 | 8-methyl-5-(4-nitrophenyl)-9H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine | C17H13N3O4 | 详情 | 详情 | |
| (III) | 35398 | 8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile | C18H14N4O4 | 详情 | 详情 | |
| (IV) | 35399 | 7-acetyl-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile | C20H16N4O5 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(VI)The condensation of 2-bromo-N,N-bis(benzyloxycarbonylmethyl)acetamide (I) with N,N'-bis(2-hydroxyethyl)ethylene-1,2-diamine (II) by means of TEA in DMF gives the corresponding bis-adduct (III). The monoacylation of (III) with butyryl chloride (IV) and DMAP in THF yields the monobutyrate (V), which is acylated with acetyl chloride (VI) and DMAP in THF affording the mixed diester monoacetate monobutyrate (VII). The deprotection of (VII) by hydrogenation with H2 over Pd/C in ethanol provides the tetraacetic acid (VIII), which is finally treated with gadolinium trichloride and NaOH to furnish the target compound.
| 【1】 Saab-Ismail, N.H.; et al.; Synthesis and in vivo evaluation of new contrast agents for cardiac MRI. J Med Chem 1999, 42, 15, 2852. |
| 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) | 38376 | benzyl 2-[[2-(benzyloxy)-2-oxoethyl](2-bromoacetyl)amino]acetate | C20H20BrNO5 | 详情 | 详情 | |
| (II) | 38377 | 2-([2-[(2-hydroxyethyl)amino]ethyl]amino)-1-ethanol | 4439-20-7 | C6H16N2O2 | 详情 | 详情 |
| (III) | 38378 | dibenzyl 3,12-bis[2-(benzyloxy)-2-oxoethyl]-6,9-bis(2-hydroxyethyl)-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioate | C46H54N4O12 | 详情 | 详情 | |
| (IV) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (V) | 38379 | dibenzyl 3,12-bis[2-(benzyloxy)-2-oxoethyl]-6-[2-(butyryloxy)ethyl]-9-(2-hydroxyethyl)-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioate | C50H60N4O13 | 详情 | 详情 | |
| (VI) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (VII) | 38380 | dibenzyl 6-[2-(acetoxy)ethyl]-3,12-bis[2-(benzyloxy)-2-oxoethyl]-9-[2-(butyryloxy)ethyl]-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioate | C52H62N4O14 | 详情 | 详情 | |
| (VIII) | 38381 | 6-[2-(acetoxy)ethyl]-9-[2-(butyryloxy)ethyl]-3,12-bis(carboxymethyl)-4,11-dioxo-3,6,9,12-tetraazatetradecane-1,14-dioic acid | C24H38N4O14 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：3-Acetylbenzonitrile (I) was protected as the ethylene ketal (II) employing ethylene glycol and boron trifluoride etherate. Reduction of the cyano group of (II) with LiAlH4 gave amine (III), and further ketal hydrolysis provided 3-acetylbenzylamine (IV). This was acetylated using acetyl chloride and Et3N to yield the intermediate amide (V). Alternatively, intermediate (V) was obtained by addition of methylmagnesium bromide to N-(3-cyanobenzyl)acetamide (VI). Bromination of (V) in dioxan furnished the bromoacetophenone (VII). This was cyclized to the aminothiazole (IX) by treatment with thiourea (VIII) in refluxing ethanol. Condensation of (IX) with benzoyl isothiocyanate (X) provided the benzoyl thiourea (XI). After selective hydrolysis of the benzoyl group of (XI) with NaOH in MeOH-H2O at 60 C, the resulting thiourea (XII) was methylated with iodomethane yielding S-methylisothiourea (XIII). Finally, displacement of the methylthio group with 2-methoxyetylamine (XIV) furnished the title guanidinothiazole.
| 【1】 Katsura, Y.; Tomishi, T.; Inoue, Y.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Guanidino thiazoles and their use as H2-receptor antagonist. EP 0545376; JP 1994321921; US 5532258 . |
| 【2】 Inoue, Y.; Morinaga, C.; Ishikawa, H.; Takasugi, H.; Tomishi, T.; Matsumoto, Y.; Katsura, Y.; Sakane, K.; Anti-Helicobacter pylori agents.4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives. J Med Chem 2000, 43, 17, 3315. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 33623 | bromo(methyl)magnesium | 75-16-1 | CH3BrMg | 详情 | 详情 | |
| (I) | 17992 | m-Cyanoacetophenone; 3-acetylbenzonitrile | 6136-68-1 | C9H7NO | 详情 | 详情 |
| (II) | 34665 | 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile | C11H11NO2 | 详情 | 详情 | |
| (III) | 34673 | 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine; [3-(2-methyl-1,3-dioxolan-2-yl)phenyl]methanamine | C11H15NO2 | 详情 | 详情 | |
| (IV) | 34666 | 1-[3-(aminomethyl)phenyl]-1-ethanone | C9H11NO | 详情 | 详情 | |
| (V) | 34674 | N-(3-acetylbenzyl)acetamide | C11H13NO2 | 详情 | 详情 | |
| (VI) | 34667 | N-(3-cyanobenzyl)acetamide | C10H10N2O | 详情 | 详情 | |
| (VII) | 34668 | N-[3-(2-bromoacetyl)benzyl]acetamide | C11H12BrNO2 | 详情 | 详情 | |
| (VIII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IX) | 34669 | N-[3-(2-amino-1,3-thiazol-4-yl)benzyl]acetamide | C12H13N3OS | 详情 | 详情 | |
| (X) | 23530 | benzoyl isothiocyanate | 532-55-8 | C8H5NOS | 详情 | 详情 |
| (XI) | 34670 | N-[3-(2-[[(benzoylamino)carbothioyl]amino]-1,3-thiazol-4-yl)benzyl]acetamide | C20H18N4O2S2 | 详情 | 详情 | |
| (XII) | 34671 | N-(3-[2-[(aminocarbothioyl)amino]-1,3-thiazol-4-yl]benzyl)acetamide | C13H14N4OS2 | 详情 | 详情 | |
| (XIII) | 34672 | 4-[3-[(acetamido)methyl]phenyl]-2-[[(E)-amino(methylsulfanyl)methylidene]amino]-1,3-thiazole | C14H16N4OS2 | 详情 | 详情 | |
| (XIV) | 34675 | 2-methoxyethylamine; 2-methoxy-1-ethanamine | 109-85-3 | C3H9NO | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(VIII)The condensation of 2,3-dihydrobenzodioxin-6-carbaldehyde (I) with 5(S)-phenylmorpholin-2-one (I) in refluxing toluene gives the adduct (III), which is treated first with pyrrolidine (IV) in chloroform and then with HCl in refluxing methanol to yield the pyrrolidide (V). The reduction of (V) with LiAlH4 in THF affords compound (VI), which is treated with H2 over Pd/C in THF/methanol/water to provide the aminoalcohol (VII). Finally, the amino group of (VII) is acylated by means of palmitoyl chloride (VIII) and DIEA in dichloromethane to furnish the target palmitoylamide.
| 【1】 Hirth, B.H.; Siegel, C. (Genzyme Corp.); Synthesis of UDP-glucose: N-Acylsphingosine glucosyltransferase inhibitors. US 2003050299; WO 0308399 . |
| 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) | 61797 | 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde; 1,4-Benzodioxan-6-carboxaldehyde; 3,4-ethylenedioxybenzaldehyde ;benzodioxane-6-carboxaldehyde | 29668-44-8 | C9H8O3 | 详情 | 详情 |
| (II) | 61798 | (5S)-5-phenyl-2-morpholinone;5(S)-phenylmorpholin-2-one;(5S)-3,4,5,6-Tetrahydro-5-phenyl-4(H)-1,4-oxazin-2-one | 144896-92-4 | C10H11NO2 | 详情 | 详情 |
| (III) | 61799 | (1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one | C28H25NO7 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 61800 | (2R,3R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2-[(2-hydroxy-1-phenylethyl)amino]-1-(1-pyrrolidinyl)-1-propanone | C23H28N2O5 | 详情 | 详情 | |
| (VI) | 61801 | (1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-3-(1-pyrrolidinyl)-1-propanol | C23H30N2O4 | 详情 | 详情 | |
| (VII) | 61802 | (1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-pyrrolidinyl)-1-propanol | C15H22N2O3 | 详情 | 详情 | |
| (VIII) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(V)Swern oxidation of derivative (I) by means of oxalyl chloride and DMSO in CH2Cl2 followed by Wittig reaction with MePPh3Br and BuLi in THF yields alkene (II), which is then converted into alcohol (III) by hydroboration with 9-BBN in EtOH and oxidation with NaOH and H2O2 in THF followed by isomer separation. Benzylation of (III) by means of NaH and BnBr (IV) in DMF, followed by hydrolysis with acetyl chloride (V) in CH2Cl2/MeOH, affords derivative (VI), which is further benzylated with BnBr (IV) and NaH in DMF and then hydrolyzed with HCl in MeOH to provide diol (VII). Derivative (VII) is O-stannylated by means of Bu2SnO in refluxing toluene and selectively allylated with allyl bromide and CsF to furnish compound (VIII), which is then benzylated with BnBr (IV) and NaH in DMF to give completely protected derivative (IX). Removal of the allyl group of (IX) is then performed by catalytic treatment with RhCl(PPh3)3 and DABCO in refluxing EtOH, and subsequent hydrolysis with HCl in refluxing acetone yields inositol derivative (X). Conversion of (X) into protected phosphatidylinositol (XII) is then performed by a standard phosphitylation protocol with BnOP(N-i-Pr2)2 and diisopropylamine-tetrazole, followed by treatment with the imidazolyl derivative (XI) in the presence of tetrazole and final adjustment of the oxidation state of the P atom by means of tert-BuOOH. Finally, hydrogenolysis of the benzyl groups of compound (XII) with Pd(OH)2/C in tert-butanol gives the desired phosphate.
| 【1】 Hu, Y.; et al.; 3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, Akt, and cancer cell growth. J Med Chem 2000, 43, 16, 3045. |
| 【2】 Meuillet, E.J.; Kozikowski, A.P.; Hu, Y.; Berggren, M.; Powis, G.; 3-Deoxy-3-substituted-D-myo-inositol imidazolyl ether lipid phosphates and carbonate as inhibitors of the phosphatidylinositol 3-kinase pathway and cancer cell growth. Bioorg Med Chem Lett 2001, 11, 2, 173. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (I) | 48135 | (3aR,4aR,7aR,8aS)-8-(benzyloxy)-2,2,6,6-tetramethylhexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-ol | C19H26O6 | 详情 | 详情 | |
| (II) | 48136 | (3aR,4aS,7aR,8aR)-4-(benzyloxy)-2,2,6,6-tetramethyl-8-methylenehexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxole; (3aR,4aS,7aR,8aR)-2,2,6,6-tetramethyl-8-methylenehexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-yl benzyl ether | C20H26O5 | 详情 | 详情 | |
| (III) | 48137 | [(3aR,4aR,7aR,8aS)-8-(benzyloxy)-2,2,6,6-tetramethylhexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-yl]methanol | C20H28O6 | 详情 | 详情 | |
| (IV) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (V) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (VI) | 48138 | (3aS,4R,5S,6R,7S,7aR)-4-(benzyloxy)-7-[(benzyloxy)methyl]-2,2-dimethylhexahydro-1,3-benzodioxole-5,6-diol | C24H30O6 | 详情 | 详情 | |
| (VII) | 48139 | (1R,2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-1,2-cyclohexanediol | C35H38O6 | 详情 | 详情 | |
| (VIII) | 48140 | (1R,2R,3S,4S,5R,6R)-2-(allyloxy)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]cyclohexanol | C38H42O6 | 详情 | 详情 | |
| (IX) | 48141 | 1-[([(1S,2R,3R,4R,5R,6S)-2-(allyloxy)-3,5,6-tris(benzyloxy)-4-[(benzyloxy)methyl]cyclohexyl]oxy)methyl]benzene; allyl (1R,2S,3S,4R,5R,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl ether | C45H48O6 | 详情 | 详情 | |
| (X) | 48142 | (1R,2S,3S,4R,5R,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexanol | C42H44O6 | 详情 | 详情 | |
| (XI) | 48143 | (2R)-2-(1H-imidazol-1-yl)-3-(octadecyloxy)-1-propanol | C24H46N2O2 | 详情 | 详情 | |
| (XII) | 48144 | benzyl (2S)-2-(1H-imidazol-1-yl)-3-(octadecyloxy)propyl (1R,2R,3S,4R,5S,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl phosphate | C73H95N2O10P | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(IV)Conversion of alpha-benzoyl-homoveratronitrile (I) into benzopyrylium perchlorate derivative (II) is performed by reaction with perchloric acid in acetic anhydride. The desired compound is then obtained by treatment of (II) with hydrazine hydrate in refluxing acetonitrile. Alternatively, the target product can be obtained as follows: Treatment of homoveratronitrile derivative (I) with hydrazine hydrate in refluxing acetic acid yields pyrazole (III), which is then acylated with acetyl chloride (IV) by means of Et3N in refluxing benzene to furnish acetylamino derivative (V). Finally, cyclization is induced by treatment of (V) with perchloric acid in refluxing acetic anhydride/nitromethane.
| 【1】 Nikolyukin, Y.A.; et al.; Synthesis of azolo(5,4-c) isoquinolines. Chem Heterocycl Compd 1990, 26, 914. |
| 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) | 48918 | 2-(3,4-dimethoxyphenyl)-3-oxo-3-phenylpropanenitrile | C17H15NO3 | 详情 | 详情 | |
| (II) | 48919 | 4-cyano-6,7-dimethoxy-1-methyl-3-phenylisochromenium perchlorate | C19H16ClNO7 | 详情 | 详情 | |
| (III) | 48920 | 4-(3,4-dimethoxyphenyl)-3-phenyl-1H-pyrazol-5-amine; 4-(3,4-dimethoxyphenyl)-3-phenyl-1H-pyrazol-5-ylamine | C17H17N3O2 | 详情 | 详情 | |
| (IV) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (V) | 48921 | N-[4-(3,4-dimethoxyphenyl)-3-phenyl-1H-pyrazol-5-yl]acetamide | C19H19N3O3 | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(II)Friedel–Crafts acylation of 2-tert-butylphenol (I) with acetyl chloride (II) in the presence of AlCl3 in cold toluene gives 1-(3-tert-butyl-4-hydroxyphenyl)ethanone (III) (1, 2), which by nitration with HNO3 in cold H2O/CH2Cl2 provides 1-(3-tert-butyl-4-hydroxy-5-nitrophenyl)ethanone (IV). O-Alkylation of phenol (IV) with methyl iodide by means of K2CO3 in DMF produces the methyl ether (V), which is reduced at the nitro group with Fe and NH4Cl in EtOH/H2O to afford the corresponding amine (VI). Cyclocondensation of the aniline derivative (VI) with bis(2-bromoethyl) ether (VII) by means of NaI and K2CO3 in DMF provides the 3-morpholino-acetophenone derivative (VIII). α-Halogenation of acetophenone (VIII) with NBS by means of Et3N and TBDMSOTf in THF yields the corresponding bromoacetophenone (IX) , which is finally condensed with isoindole derivative (X) in THF or DMF .
The isoindole intermediate (X) is prepared by dialkylation of 3-fluorocatechol (XI) with ethyl iodide (XII) in the presence of K2CO3 in DMF to give 1,2-diethoxy-3-fluorobenzene (XIII), which is brominated with Br2 by means of NaOAc in AcOH at 70 °C to yield 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (XIV). Bromide substitution in intermediate (XIV) with CuCN in DMF at 150 °C affords 4,5-diethoxy-3-fluorophthalonitrile (XV), which is finally submitted to reductive cyclization with H2 over PtO2 in EtOAc/EtOH/MeOH .
| 【1】 Suzuki, S., Naoe, Y., Miyamoto, M. et al. (Eisai R&D Management Co., Ltd.). 2-Iminopyrrolidine derivatives. EP 1391451, EP 2385039, US 2005004204, US 7244730, WO 2002085855. |
| 【2】 Shimomura, N., Sasho, M., Kayano, A., Yoshizawa, K., Tsujii, M., Kuroda,H., Furukawa, K. (Eisai R&D Management Co., Ltd.). Processes for producing cyclic benzamidine derivative. CA 2515715, EP 1602646, US 2006058370, US 7375236, WO 2004078721. |
| 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) | 67678 | 2-tert-butylphenol；o-t-Butylphenol；o-tert-Butylphenol；2-tert-Butyl-1-hydroxybenzene；2-(1,1-Dimethylethyl)phenol | 88-18-6 | C10H14O | 详情 | 详情 |
| (II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (III) | 68400 | 1-(3-tert-butyl-4-hydroxyphenyl)ethanone | C12H16O2 | 详情 | 详情 | |
| (IV) | 68401 | 1-(3-(tert-butyl)-4-hydroxy-5-nitrophenyl)ethanone | C12H15NO4 | 详情 | 详情 | |
| (V) | 68402 | 1-(3-(tert-butyl)-4-methoxy-5-nitrophenyl)ethanone | C13H17NO4 | 详情 | 详情 | |
| (VI) | 68403 | 1-(3-amino-5-(tert-butyl)-4-methoxyphenyl)ethanone | C13H19NO2 | 详情 | 详情 | |
| (VII) | 63502 | 1-bromo-2-[(2-bromoethyl)oxy]ethane; bis(2-bromoethyl) ether | 5414-19-7 | C4H8Br2O | 详情 | 详情 |
| (VIII) | 68404 | 1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone | C17H25NO3 | 详情 | 详情 | |
| (IX) | 68405 | 2-bromo-1-(3-(tert-butyl)-4-methoxy-5-morpholinophenyl)ethanone | C17H24BrNO3 | 详情 | 详情 | |
| (X) | 68406 | 5,6-diethoxy-4-fluoro-1H-isoindol-3-amine | C12H15FN2O2 | 详情 | 详情 | |
| (XI) | 68407 | 3-fluorocatechol;3-FLUORO-1,2-DIHYDROXYBENZENE;3-FLUOROBENZENE-1,2-DIOL;1-FLUORO-2,3-DIHYDROXYBENZENE;1,2-Dihydroxy-3-fluoroBenzene | 363-52-0 | C6H5FO2 | 详情 | 详情 |
| (XII) | 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 |
| (XIII) | 68408 | 1,2-diethoxy-3-fluorobenzene | C10H13FO2 | 详情 | 详情 | |
| (XIV) | 68409 | 1,2-dibromo-4,5-diethoxy-3-fluorobenzene | C10H11Br2FO2 | 详情 | 详情 | |
| (XV) | 68410 | 4,5-diethoxy-3-fluorophthalonitrile;6-(aminomethyl)-3,4-diethoxy-2-fluorobenzonitrile | 474554-45-5 | C12H11FN2O2 | 详情 | 详情 |