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【结 构 式】 
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【分子编号】25890 【品名】2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride 【CA登记号】103-80-0 |
【 分 子 式 】C8H7ClO 【 分 子 量 】154.59568 【元素组成】C 62.15% H 4.56% Cl 22.93% O 10.35% |
合成路线1
该中间体在本合成路线中的序号：(VII)6-(Tritylamino)penicillanic acid (I) is converted into the azetidinone (II), which is treated with p-toluenesulfonic acid to yield the tosylate (III). The chlorination of (III) with Cl2 in carbon tetrachloride affords the 4-chloroazetidinone (IV), which is condensed with propargyl alcohol (V) by means of AgBF4 in THF to give the propargyl ether (VI) as a mixture of cis and trans isomers that is separated by chromatography. The acylation of (VI) with phenylacetyl chloride (VII) and pyridine affords the amide (VIII).
| 【1】 Narisada, M.; et al.; Synthetic studies on beta-lactam antibiotics. Part 5. A synthesis of 7beta-acylamino-3-methyl-1-oxadethia-3-cephem-4-carboxylic acids. Heterocycles 1977, 7, 2, 839. |
| 【2】 Nagata, W.; Narisada, M. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. US 4180571 . |
| 【3】 Narisada, M.; Nagata, W. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. DE 2713370; US 4138486 . |
| 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) | 38581 | Benzhydryl (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(tritylamino)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C40H36N2O3S | 详情 | 详情 | |
| (II) | 38582 | 1-phenylethyl 3-methyl-2-[(2R,3R)-2-(methylsulfanyl)-4-oxo-3-(tritylamino)azetidinyl]-2-butenoate | C36H36N2O3S | 详情 | 详情 | |
| (III) | 38583 | 1-phenylethyl 2-[(2R,3R)-3-amino-2-(methylsulfanyl)-4-oxoazetidinyl]-3-methyl-2-butenoate | C17H22N2O3S | 详情 | 详情 | |
| (IV) | 38584 | 1-phenylethyl 2-[(3R)-3-amino-2-chloro-4-oxoazetidinyl]-3-methyl-2-butenoate | C16H19ClN2O3 | 详情 | 详情 | |
| (V) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (VI) | 38585 | 1-phenylethyl 2-[(3S,4R)-3-amino-2-oxo-4-(2-propynyloxy)azetidinyl]-3-methyl-2-butenoate | C19H22N2O4 | 详情 | 详情 | |
| (VII) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (VIII) | 38586 | 1-phenylethyl 3-methyl-2-[(3S,4R)-2-oxo-3-[(2-phenylacetyl)amino]-4-(2-propynyloxy)azetidinyl]-2-butenoate | C27H28N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The condensation of 2,3-dichloroanisole (I) with phenylacetyl chloride (A) by means of AlCl3 in CS2 gives 2,3-dichloro-4-phenylacetylanisole (II), which by reaction with bis(dimethylamino)methane (B) in acetic anhydride is converted into 2,3-dichloro-4-(2-phenylacryloyl)anisole (III). The cyclization of (III) by means of H2SO4 yields 6,7-dichloro-2-phenyl-5-methoxy-1-indanone (IV), which by demethylation with pyridine hydrochloride at 190 C yields 6,7-dichloro-2-phenyl-5-hydroxy-1-indadone (V). The treatment of the phenol (V) with iodoacetic acid (C) and K2CO3 in acetone affords 6,7-dichloro-2-phenyl-1-oxo-5-indanyloxyacetic acid (VI), which is finally methylated with methyl iodide and NaH in DMF.
| 【1】 Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.); Substituted indanones. DE 2448454; ES 430900; FR 2247218; GB 1474459 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179. |
| 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) | 14349 | N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine | 51-80-9 | C5H14N2 | 详情 | 详情 |
| (A) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (I) | 40081 | 1,2-dichloro-3-methoxybenzene; 2,3-dichlorophenyl methyl ether | 1984-59-4 | C7H6Cl2O | 详情 | 详情 |
| (II) | 40082 | 1-(2,3-dichloro-4-methoxyphenyl)-2-phenyl-1-ethanone | C15H12Cl2O2 | 详情 | 详情 | |
| (III) | 40083 | 1-(2,3-dichloro-4-methoxyphenyl)-2-phenyl-2-propen-1-one | C16H12Cl2O2 | 详情 | 详情 | |
| (IV) | 40084 | 6,7-dichloro-5-methoxy-2-phenyl-1-indanone | C16H12Cl2O2 | 详情 | 详情 | |
| (V) | 40085 | 6,7-dichloro-5-hydroxy-2-phenyl-1-indanone | C15H10Cl2O2 | 详情 | 详情 | |
| (VI) | 40087 | 2-[(6,7-dichloro-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid | C17H12Cl2O4 | 详情 | 详情 | |
| (C) | 40086 | 2-iodoacetic acid | 64-69-7 | C2H3IO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Using a different protection strategy, aminoacid (IV) was protected as the N-phenylacetyl derivative (VII) by treatment with acid chloride (VI). Subsequent DCC-mediated coupling with the cephem derivative (III) furnished (VIII). The N-phenylacetyl group was then selectively removed by enzymatic hydrolysis with penicillin G amidase.
| 【1】 Zenoni, M.; Fuganti, C.; A method for the acylation of the 7-amino group of the cephalosporanic ring. EP 0582102 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56514 | 7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H15N3O5S3 | 详情 | 详情 | |
| (IV) | 24737 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid | 65872-41-5 | C6H7N3O3S | 详情 | 详情 |
| (VI) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (VII) | 56516 | 2-(methoxyimino)-2-{2-[(2-phenylacetyl)amino]-1,3-thiazol-4-yl}acetic acid | C14H13N3O4S | 详情 | 详情 | |
| (VIII) | 56517 | 3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-7-[(2-(methoxyimino)-2-{2-[(2-phenylacetyl)amino]-1,3-thiazol-4-yl}acetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C28H26N6O8S4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(A)The reaction of p-chloroaniline (I) with ethyl 4-oxopiperidine-1-carboxylate (II) by means of tosyl chloride in refluxing toluene gives ethyl 4-(p-chlorophenylimino)piperidine-1-carboxylate (III), which is reduced with NaBH4 in refluxing methanol to afford ethyl 4-(p-chloroanilino)piperidine-1-carboxylate (IV). The acylation of (IV) with phenylacetyl chloride (A) in refluxing benzene yields ethyl 4-[N-(p-chlorophenyl)-N-(phenylacetyl)amino]piperidine-1-carboxylate (V), which is decarboxylated with hot aqueous HBr giving N-(p-chlorophenyl)-N-(piperidin-4-yl)phenylacetamide hydrochloride (VI). Finally, this compound is alkylated with 2-bromopropane (B) and Na2CO3 in refluxing butanol.
| 【1】 Hermans, H.K.; Sanczuk, S.; N-aryl-N-(1-L-4-piperidinyl)-arylacetamides. BE 0846473; US 4151286; US 4157393; ZA 7605684 . |
| 【2】 Castaner, J.; Weetman, D.F.; Lorcainide hydrochloride. Drugs Fut 1978, 3, 7, 518. |
| 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) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (B) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (I) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (II) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (III) | 33565 | ethyl 4-[(4-chlorophenyl)imino]-1-piperidinecarboxylate | C14H17ClN2O2 | 详情 | 详情 | |
| (IV) | 33566 | ethyl 4-(4-chloroanilino)-1-piperidinecarboxylate | C14H19ClN2O2 | 详情 | 详情 | |
| (V) | 33567 | ethyl 4-[4-chloro(2-phenylacetyl)anilino]-1-piperidinecarboxylate | C22H25ClN2O3 | 详情 | 详情 | |
| (VI) | 33568 | N-(4-chlorophenyl)-2-phenyl-N-(4-piperidinyl)acetamide | C19H21ClN2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The acylation of 3-(2-naphthyl)-D-alanine (I) with phenylacetyl chloride (II) and bis(trimethylsilyl)acetamide in THF gives the expected N-phenylacetyl derivative (III), which is methylated with NaH and methyl iodide in THF yielding the N-methyl derivative (IV). The reaction of (IV) with 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (WSC), HOBT and ammonium hydroxide affords the corresponding alaninamide (V), which by reaction with bis(trifluoroacetoxy)iodobenzene (BTI) in acetonitrile is converted into the monoacylated gemdiamine (VI). The condensation of (VI) with cis-2-(1H-indol-3-ylcarboxamido)cyclohexanecarboxylic acid (VII) by means of WSC and HOBT in DMF affords the target compound as a diastereomeric mixture that is separated by preparative RP-HPLC.
| 【1】 Sisto, A.; Fincham, C.; Potier, E.; Manzini, S.; Arcamone, F.; Lombardi, P. (Malesci Ist. Farmacobiol. SpA; Menarini Industrie Farma Riunite srl); Tachykinin antagonists. EP 0731790; JP 1997506348; US 5760248; WO 9515311 . |
| 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) | 21016 | (2R)-2-amino-3-(2-naphthyl)propionic acid; D-3-(2-Naphthyl)alanine | 76985-09-6 | C13H13NO2 | 详情 | 详情 |
| (II) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (III) | 25891 | (2R)-3-(2-naphthyl)-2-[(2-phenylacetyl)amino]propionic acid | C21H19NO3 | 详情 | 详情 | |
| (IV) | 25892 | (2R)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propionic acid | C22H21NO3 | 详情 | 详情 | |
| (V) | 25893 | (2R)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propanamide | C22H22N2O2 | 详情 | 详情 | |
| (VI) | 25894 | N-[(1R)-1-amino-2-(2-naphthyl)ethyl]-N-methyl-2-phenylacetamide | C21H22N2O | 详情 | 详情 | |
| (VII) | 25895 | (1R,2S)-2-[(1H-indol-3-ylcarbonyl)amino]cyclohexanecarboxylic acid | C16H18N2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Knoevenagel condensation of pyridine-3-carboxaldehyde (I) with malonic acid in the presence of ammonium acetate afforded the racemic amino acid (III), which was acylated with phenylacetyl chloride (IV) to give amide (V). Optical resolution of (V) by means of penicillin amidase produced the hydrolysis of the undesired (R)-enantiomer. After isolation of the unreacted (S)-enantiomer (VI), its hydrolysis with aqueous HCl furnished the chiral amino acid (VII), which was converted to methyl ester (VIII) with 2,2-dimethoxypropane in MeOH. Coupling of (VIII) with N-Boc-(R)-nipecotic acid (IX) using 2-benzotriazolyl-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) provided amide (X). Deprotection of the Boc group of (X) was then achieved with HCl in dioxan resulting amine (XI).
| 【1】 Hoekstra, W.J.; Damiano, B.P.; Maryanoff, B.E.; et al.; Potent orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure - Activity studies leading to the discovery of RWJ-53308. J Med Chem 1999, 42, 25, 5254. |
| 【2】 Costanzo, M.J.; Hoekstra, W.J.; Maryanoff, B.E. (Ortho-McNeil Pharmaceutical, Inc.); Carboxamide derivs. of pyrrolidine, piperidine and hexahydroazepine for the treatment of thrombosis disorders. EP 0923555; JP 2000510111; US 6069254; WO 9741102 . |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (III) | 27468 | 3-(3-pyridinyl)-beta-alanine | C8H10N2O2 | 详情 | 详情 | |
| (IV) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (V) | 27469 | N-(2-phenylacetyl)-3-(3-pyridinyl)-beta-alanine | C16H16N2O3 | 详情 | 详情 | |
| (VI) | 27470 | (3S)-3-[(2-phenylacetyl)amino]-3-(3-pyridinyl)propionic acid | C16H16N2O3 | 详情 | 详情 | |
| (VII) | 27471 | (3S)-3-amino-3-(3-pyridinyl)propionic acid | C8H10N2O2 | 详情 | 详情 | |
| (VIII) | 27472 | methyl (3S)-3-amino-3-(3-pyridinyl)propanoate | C9H12N2O2 | 详情 | 详情 | |
| (IX) | 27473 | (3R)-1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (X) | 27474 | tert-butyl (3R)-3-([[(1S)-3-methoxy-3-oxo-1-(3-pyridinyl)propyl]amino]carbonyl)-1-piperidinecarboxylate | C20H29N3O5 | 详情 | 详情 | |
| (XI) | 27475 | methyl (3S)-3-[[(3R)piperidinylcarbonyl]amino]-3-(3-pyridinyl)propanoate | C15H21N3O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Acylation of 2-amino-5-nitrobenzophenone (I) with phenylacetic acid chloride (II) in refluxing toluene yields derivative (III), whose nitro group is reduced by means of SnCl2 in refluxing EtOAc to afford amine (IV). Coupling of (IV) with protected cysteine (V) by means of isobutyl chloroformate and N-methylmorpholine (NMM) in DMF provides protected derivative (VI), which is finally treated with TFA and Et3SiH in CH2Cl2 to furnish the target compound.
| 【1】 Schlitzer, M.; et al.; Different amino acid replacement in CAAX-tetrapeptide based peptidomimetic farnesyltransferase inhibitors. Archiv der Pharmazie 1999, 332, 4, 124. |
| 【2】 Grabley, S.; Thiericke, R.; Sattler, I. (Hans Knoll Institute for Natural Product Research); Cysteine amides as farnesyl transferase inhibitors. DE 19851714; WO 0027803 . |
| 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) | 43770 | (2-amino-5-nitrophenyl)(phenyl)methanone | 1775-95-7 | C13H10N2O3 | 详情 | 详情 |
| (II) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (III) | 43371 | 4-(2,4-dimethoxy-6-methylphenyl)-3-methyl-1H-pyrazol-5-ylamine; 4-(2,4-dimethoxy-6-methylphenyl)-3-methyl-1H-pyrazol-5-amine | C13H17N3O2 | 详情 | 详情 | |
| (IV) | 43772 | N-(4-amino-2-benzoylphenyl)-2-phenylacetamide | C21H18N2O2 | 详情 | 详情 | |
| (V) | 38791 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propionic acid | 21947-98-8 | C27H29NO4S | 详情 | 详情 |
| (VI) | 43773 | tert-butyl (1R)-2-[3-benzoyl-4-[(2-phenylacetyl)amino]anilino]-2-oxo-1-[(tritylsulfanyl)methyl]ethylcarbamate | C48H45N3O5S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Treatment of phenylacetyl chloride (I) with tris(trimethylsilyloxy)ethylene (A) in the presence of SnCl4 affords 1-hydroxy-3-phenylpropan-2-one (II), which is then condensed with ethyl oxalyl chloride (III) in THF in the presence of Et3N to yield (IV). Phenylhexanoate derivative (IV) is cyclized by means of DBU in DMF to provide valerolactone derivative (V), which is then condensed with 1-methylindole-3-carboxaldehyde (VI) in HOAc to furnish derivative (VII). Finally, the target compound is obtained by treatment of (VII) with NaOMe in MeOH.
| 【1】 Liu, K.; Szalkowski, D.; Xu, L.; et al.; Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor. J Med Chem 2000, 43, 19, 3487. |
| 【2】 Wood, H.B.; Jones, A.B.; Zhang, B.; Liu, K. (Merck & Co., Inc.); Antidiabetic agents. EP 1067925; US 6077849; WO 9951225 . |
| 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) | 14534 | 2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE | 69097-20-7 | C11H28O3Si3 | 详情 | 详情 |
| (I) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (II) | 45469 | 2-phenylethaneperoxoic acid | C8H8O3 | 详情 | 详情 | |
| (III) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IV) | 45470 | ethyl 2-oxo-2-[(2-phenylacetyl)peroxy]acetate | C12H12O6 | 详情 | 详情 | |
| (V) | 45471 | 3-hydroxy-4-phenyl-2H-pyran-2,5(6H)-dione | C11H8O4 | 详情 | 详情 | |
| (VI) | 45472 | 1-Methylindole-3-carboxaldehyde; 1-Methyl-1H-indole-3-carbaldehyde; 1-Methylindole-3-carbaldehyde | 19012-03-4 | C10H9NO | 详情 | 详情 |
| (VII) | 45473 | 3-hydroxy-6-[(Z)-(3-methyl-3H-benzimidazol-1-yl)methylidene]-4-phenyl-2H-pyran-2,5-dione | 455-15-2 | C20H16N2O4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Friedel-Crafts acylation of 3-methoxyphenol (I) with 4-hydroxyphenylacetic acid (II) in the presence of ZnCl2 and POCl3 furnished ketone (III), which was subsequently protected with triisopropylsilyl chloride and Et3N to yield the mono-silyl ether (IV). Coumarin (VI) was then synthesized by condensation of hydroxy ketone (IV) with phenylacetyl chloride (V) in the presence of K2CO3. Alkylation of the phenolic hydroxyl group of (VI) with N-(2-chloroethyl)piperidine (VII) gave the piperidinylethyl ether (VIII). Finally, selective methyl ether hydrolysis using HBr in refluxing HOAc led to the title compound.
| 【1】 Bhagwat, S.S.; McKie, J.A.; Khammungkhune, S. (Signal Pharmaceuticals, Inc.); Cpds. and methods for modulation of estrogen receptors. WO 0149673 . |
| 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) | 22389 | 3-Methoxyphenol | 150-19-6 | C7H8O2 | 详情 | 详情 |
| (II) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (III) | 56078 | 1-(2-hydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C15H14O4 | 详情 | 详情 | |
| (IV) | 56079 | 1-(2-hydroxy-4-methoxyphenyl)-2-{4-[(triisopropyl-lambda~4~-sulfanyl)oxy]phenyl}-1-ethanone | C24H34O4S | 详情 | 详情 | |
| (V) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (VI) | 56080 | 4-(4-hydroxybenzyl)-7-methoxy-3-phenyl-2H-chromen-2-one | C23H18O4 | 详情 | 详情 | |
| (VII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (VIII) | 56081 | 7-methoxy-3-phenyl-4-{4-[2-(1-piperidinyl)ethoxy]benzyl}-2H-chromen-2-one | C30H31NO4 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIII)The bromo amide intermediate (XI) is prepared by condensation of phenylacetyl chloride (XIII) with N-methylhydroxylamine hydrochloride in the presence of Et3N in CH2Cl2 to produce the Weinreb amide (XIV), which is then acylated with methanesulfonyl chloride and Et3N followed by ultrasound-promoted rearrangement of the N-sulfonyloxy amide intermediate in the presence of DIEA and LiBr in acetonitrile (1). Scheme 2.
| 【1】 Weller, T., Koberstein, R., Aissaoui, H., Clozel, M., Fischli, W. (Actelion Pharmaceuticals Ltd.). Substituted 1,2,3,4-tetrahydroisoquinoline derivatives. EP 1751111, JP 2007525531, US 2007191424, WO 2005118548. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 65808 | 2-Bromo-N-Methyl-2-Phenyl-Acetamide | 51685-62-2 | C9H10BrNO | 详情 | 详情 |
| (XIII) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (XIV) | 65810 | N-Methylphenylacetohydroxamic Acid; N-Hydroxy-N-Methyl-2-Phenyl-Acetamide; N-Hydroxy-N-Methyl-2-Phenyl-Ethanamide | 72229-75-5 | C9H11NO2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XIX)Amination of 2-phenylethyl bromide (XII) with methylamine in THF gives N-methylphenethylamine (XIII) , which upon N-acylation with chloroacetyl chloride (XIV) in the presence of NaHCO3 in CH2Cl2 or methyl t-butyl ether yields the chloroacetamide derivative (XV) . Cyclization of intermediate (XV) by Friedel-Crafts alkylation by means of AlCl3 in 1,2-dichlorobenzene at 165 °C gives 3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (XVI) . Alternatively, compound (XVI) can be obtained from 2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (XVII) by N-methylation with methyl iodide by means of NaH in DMF . Treatment of lactam (XVI) with isoamyl nitrite (i-AmONO) in the presence of NaHMDS or LiHMDS in THF yields the 1-hydroxyiminobenzazepinone (XVIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C or with H2 over Raney-Ni in the presence of NH3 in EtOH at 100 °C .
Alternatively, phenylacetyl chloride (XIX) is condensed with N-(2,2-dimethoxyethyl)-N-methylamine (XX) by means of NaHCO3 in methyl t-butyl ether/H2O to furnish the phenylacetamide derivative (XXI), which upon cyclization in the presence of H2SO4 at 110 °C affords the benzazepin-2-one derivative (XXII). Treatment of intermediate (XXII) with i-AmONO in the presence of LiHMDS in THF gives the hydroxyimino derivative (XXIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C .
| 【1】 Koenig, T.M., Nissen, J.S., Mitchell, D. (Eli Lilly and Company). Lactam compound. EP 1345955, JP 2005538031, WO 2002040508. |
| 【2】 Audia, J.E., John, V., Latimer, L.H., Tung, J.S., Nissen, J.S., Thorsett, E.D., McDaniel, S.L. (Eli Lilly and Company; Elan Pharmaceuticals, Inc.). Lactam compound. JP 2004517090, WO 2002047671. |
| 【3】 Koenig, T.M., Audia, J.E., Mitchell, D., Aikins, J.A., Buccilli, L.A., Engel,G.L., McDaniel, S.L. (Eli Lilly and Company). Lactam compound. CA 2425497, EP 1353910, JP 2004521084, WO 2002040451. |
| 【4】 Audia, J.E., Diseroad, B.A., Varghese, J. et al. (Eli Lilly and Company).Lactam compound. US 2007299053, US 7468365. |
| 【5】 Mitchell, D., Hay, L.A., Koenig, T.M., McDaniel, S., Nissen, J.S., Audia, J.E.Classical and dynamic resolution of 1-amino-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one. Tetrahedron Asymmetry 2005, 16(23): 3814-9. |
| 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) | 69307 | 1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one | C11H14N2O | 详情 | 详情 | |
| (XII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (XIII) | 69316 | N-methyl-2-phenylethanamine；N-Phenethylmethylamine;N-methylphenethylamine | 589-08-2 | C9H13N | 详情 | 详情 |
| (XIV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XV) | 69317 | 2-chloro-N-methyl-N-phenethylacetamide | C11H14ClNO | 详情 | 详情 | |
| (XVI) | 69318 | 3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one；3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one | 73644-95-8 | C11H13NO | 详情 | 详情 |
| (XVII) | 69319 | 4,5-Dihydro-1H-benzo[d]azepin-2(3H)-one;1,3,4,5-Tetrahydrobenzo[d]azepin-2-one;1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one;2,3,4,5-tetrahydro-1H-3-benzazepin-2-one | 15987-50-5 | C10H11NO | 详情 | 详情 |
| (XVIII) | 69320 | (E)-1-(hydroxyimino)-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one | C11H12N2O2 | 详情 | 详情 | |
| (XIX) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (XX) | 36650 | 2,2-dimethoxy-N-methyl-1-ethanamine;1,1-Dimethoxy-2-(methylamino)-ethane;Methylaminoacetaldehyde dimethyl acetal;N-(2,2-dimethoxyethyl)-N-methylamine | 122-07-6 | C5H13NO2 | 详情 | 详情 |
| (XXI) | 69321 | N-(2,2-dimethoxyethyl)-N-methyl-2-phenylacetamide | C13H19NO3 | 详情 | 详情 | |
| (XXII) | 69322 | 3-methyl-1H-benzo[d]azepin-2(3H)-one | C11H11NO | 详情 | 详情 | |
| (XXIII) | 69323 | (E)-1-(hydroxyimino)-3-methyl-1H-benzo[d]azepin-2(3H)-one | C11H10N2O2 | 详情 | 详情 |