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【结 构 式】 
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【分子编号】20537 【品名】methyl 4-aminobenzoate 【CA登记号】619-45-4 |
【 分 子 式 】C8H9NO2 【 分 子 量 】151.165 【元素组成】C 63.56% H 6% N 9.27% O 21.17% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of p-aminobenzoic acid methyl ester (I) with methanesulfonyl chloride using pyridine as base provides the methanesulfonyl derivative (II). Heating (II) in heat N,N-diethyl-1,2-ethanediamine (III) at 140-50 C until complete disappearance of (II) gives the crude sematilide, which, after removal of excess diamine under vacuum, is crystallized as the hydrochloride salt from isopropanol/aqueous HCl.
| 【1】 Lumma, W.C. Jr.; Davey, D.D.; Wohl, R.A. (Berlex Laboratories, Inc.); Substituted sulfonamidobenzamides, antiarrhythmic agents and compositions thereof.. EP 0158775; JP 85209559; US 4544654 . |
| 【2】 Lumma, W.C. Jr.; SEMATILIDE HYDROCHLORIDE < Rec INNM; USAN >. Drugs Fut 1989, 14, 3, 234. |
合成路线2
该中间体在本合成路线中的序号：(XI)The reaction of 7-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one (I) with NaNO2 and BF4H in water gives the corresponding diazo compound (II), which is treated with H2SO4 in refluxing water yielding 7-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one (III). The reaction of (III) with trifluoromethanesulfonic anhydride in pyridine affords the expected sulfonate (IV), which is carboxylated with CO, PdAc2 and 1,3-bis(diphenylphosphino)propane in methanol/DMSO yielding 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (V). The Grignard condensation of (V) with phenylmagnesium bromide (VI) in THF affords the corresponding addition product (VII), which is dehydrated with p-toluenesulfonic acid in hot toluene affording the dihydronaphtoic ester (VIII). The hydrolysis of (VIII) with NaOH in ethanol gives the corresponding free acid (IX), which is treated with SOCl2 and DMF yielding the expected acyl chloride (X). The condensation of (X) with methyl 4-aminobenzoate (XI) in pyridine affords the expected amide (XII), which is finally hydrolyzed to the target compound with NaOH in ethanol/water.
| 【1】 Starrett, J.E. Jr.; Yu, K.-L.; Mansuri, M.M.; Tortolani, D.R. (Bristol-Myers Squibb Co.); Substd. (5,6)-dihydronaphthalenyl cpds. having retinoid-like activity. CA 2138000; EP 0661259; JP 1995242591; US 5648385 . |
| 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) | 27269 | 7-amino-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C12H15NO | 详情 | 详情 | |
| (II) | 27793 | 5,5-Dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yldiazonium tetrafluoroborate | C12H13BF4N2O | 详情 | 详情 | |
| (III) | 27794 | 7-hydroxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C12H14O2 | 详情 | 详情 | |
| (IV) | 27795 | 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl trifluoromethanesulfonate | C13H13F3O4S | 详情 | 详情 | |
| (V) | 27796 | methyl 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate | C14H16O3 | 详情 | 详情 | |
| (VI) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (VII) | 27797 | methyl 8-hydroxy-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate | C20H22O3 | 详情 | 详情 | |
| (VIII) | 27798 | methyl 5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarboxylate | C20H20O2 | 详情 | 详情 | |
| (IX) | 27799 | 5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarboxylic acid | C19H18O2 | 详情 | 详情 | |
| (X) | 27800 | 5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarbonyl chloride | C19H17ClO | 详情 | 详情 | |
| (XI) | 20537 | methyl 4-aminobenzoate | 619-45-4 | C8H9NO2 | 详情 | 详情 |
| (XII) | 27801 | methyl 4-[[(5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenyl)carbonyl]amino]benzoate | C27H25NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The condensation of L-asparagine (I) with benzenesulfonyl chloride (II) in the presence of NaOH gave sulfonamide (III). Subsequent Hofmann rearrangement of (III) employing sodium hypobromite produced the diaminopropionic acid derivative (IV), which was protected as the tert-butyl ester (V) using isobutylene in the presence of H2SO4. Condensation of methyl 4-aminobenzoate (VI) with bis(2-chloroethyl)amine (VII) in refluxing butanol yielded the arylpiperazine (VIII), which was protected with di tert-butyl dicarbonate to give the corresponding carbamate (IX). Basic hydrolysis of the methyl ester of (IX) provided carboxylic acid (X). This was then coupled with amine (V) using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) to afford amide (XI). Finally, deprotection of the tert-butyl ester and BOC group of (XI) with trifluoroacetic acid furnished the title compound.
| 【1】 Egbertson, M.S.; Turchi, L.M.; Hartman, G.D.; Halczenko, W.; Whitman, D.B.; Perkins, J.J.; Krause, A.E.; Ihle, N.; Claremon, D.A.; Hoffman, W.; Duggan, M.E. (Merck & Co., Inc.); Fibrinogen receptor antagonists. EP 0673247; JP 1996504194; WO 9412181 . |
| 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) | 25972 | S-(+)-Asparagine; S-(+)-2-Aminosuccinamic acid; L-Asparagine | 70-47-3 | C4H8N2O3 | 详情 | 详情 |
| (II) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
| (III) | 25973 | (2S)-4-amino-4-oxo-2-[(phenylsulfonyl)amino]butyric acid | C10H12N2O5S | 详情 | 详情 | |
| (IV) | 31422 | (2S)-3-amino-2-[(phenylsulfonyl)amino]propionic acid | C9H12N2O4S | 详情 | 详情 | |
| (V) | 31423 | tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C13H20N2O4S | 详情 | 详情 | |
| (VI) | 20537 | methyl 4-aminobenzoate | 619-45-4 | C8H9NO2 | 详情 | 详情 |
| (VII) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VIII) | 31424 | methyl 4-(1-piperazinyl)benzoate | C12H16N2O2 | 详情 | 详情 | |
| (IX) | 31425 | tert-butyl 4-[4-(methoxycarbonyl)phenyl]-1-piperazinecarboxylate | C17H24N2O4 | 详情 | 详情 | |
| (X) | 31426 | 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzoic acid | C16H22N2O4 | 详情 | 详情 | |
| (XI) | 31427 | tert-butyl 4-[4-[([(2S)-3-(tert-butoxy)-3-oxo-2-[(phenylsulfonyl)amino]propyl]oxy)carbonyl]phenyl]-1-piperazinecarboxylate | C29H39N3O8S | 详情 | 详情 |