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【结 构 式】 
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【分子编号】33623 【品名】bromo(methyl)magnesium 【CA登记号】75-16-1 |
【 分 子 式 】CH3BrMg 【 分 子 量 】119.24382 【元素组成】C 10.07% H 2.54% Br 67.01% Mg 20.38% |
合成路线1
该中间体在本合成路线中的序号：(A)The diazotation of 2,3-dichloroaniline (IX) with NaNO2 and HCl gives the corresponding diazonium chloride (X), which by a Sandmeyer reaction with CuCN yields 2,3-dichlorophenyl cyanide (XI). The Grignard reaction of (XI) with methylmagnesium bromide (A) in ether affords 2,3-dichloroacetophenone (XII), which by a Willgerodt reaction with S and morpholine is converted into 2,3-dichlorophenylacetic acid (XIII). The reaction of (XIII) with oxalyl chloride (B) in carbon tetrachloride affords the corresponding acyl chloride (XIV), which is cyclized with ethylene (C) by means of AlCl3 in methylene chloride yielding 7,8-dichloro-2-tetralone (XV). The reaction of (XV) with sodium azide in CHCl3 by means of H2SO4 gives 8,9-dichloro-2-benzazepin-3-one (XVI), which is finally reduced with diborane in THF.
| 【1】 Molloy, B.B.; Chlorinated tetrahydro-2-benzazepines, N-methyl transferase inhibitors. CA 1119592 . |
| 【2】 Serradell, M.N.; Castaner, J.; LY-134046. Drugs Fut 1984, 9, 4, 268. |
| 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) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (A) | 33623 | bromo(methyl)magnesium | 75-16-1 | CH3BrMg | 详情 | 详情 |
| (IX) | 28562 | 2,3-dichlorophenylamine | 608-27-5 | C6H5Cl2N | 详情 | 详情 |
| (X) | 34165 | 2,3-dichlorobenzenediazonium chloride | C6H3Cl3N2 | 详情 | 详情 | |
| (XI) | 30204 | 2,3-dichlorobenzonitrile | 6574-97-6 | C7H3Cl2N | 详情 | 详情 |
| (XII) | 34166 | 1-(2,3-dichlorophenyl)-1-ethanone | C8H6Cl2O | 详情 | 详情 | |
| (XIII) | 34167 | 2-(2,3-dichlorophenyl)acetic acid | C8H6Cl2O2 | 详情 | 详情 | |
| (XIV) | 34168 | 2-(2,3-dichlorophenyl)acetyl chloride | C8H5Cl3O | 详情 | 详情 | |
| (XV) | 34169 | 7,8-dichloro-3,4-dihydro-2(1H)-naphthalenone | C10H8Cl2O | 详情 | 详情 | |
| (XVI) | 34170 | 8,9-dichloro-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one | C10H9Cl2NO | 详情 | 详情 | |
| (C) | 28363 | ethylene | 9002-88-4 | C2H4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(B)Compound can be prepared in two different ways: 1) By dehydration of 13beta-ethyl-11beta,17beta-dihydroxy-17alpha-ethynyl-gona-4,9-diene-3-one (IV) with 60% formic acid at 100 C or with perchloric acid in methylene chloride containing acetonitrile. 2) The ketalization of 13beta-ethyl-gona-4,9,11-triene-3,17-dione (I) by means of glycol (A) and oxalic acid in dichloroethane affords 3-ethylenedioxy-13beta-ethyl-gona-4,9,11-trien-17-one (II), which is then treated with methylmagnesium bromide (B) and acetylene (C) in THF to yield 3-ethylenedioxy-13beta-ethyl-17beta-hydroxy-17alpha-ethynyl-gona-4,9,11-triene (III). Finally, this compound is hydrolyzed in an acidic medium.
| 【1】 Bertin, D.; Pierdet, A.; 19-Nor-delta(4,9,11)-gonatriene-3-ones. DE 1618810; FR 1503984; GB 1128787; US 3484462 . |
| 【2】 Bertin, D.; Pierdet, A; Process for the preparation of unsaturated 19-nor steroids. DE 1618815; FR 1479352; GB 1128788; US 3478067 . |
| 【3】 Nomine, G.; et al.; New Steroid compounds, compositions incorporating them and processes for their preparation. GB 1069709 . |
| 【4】 Nomine, G.; et al.; Novel 13beta-alkyl-4,9,11-gonatriene-3-ones. DE 1291337; DE 1593307; FR 1426077; FR 1453214; FR 1492782; NL 6607609; US 3248294; US 3257278 . |
| 【5】 Castaner, J.; Thorpe, P.; R-2323. Drugs Fut 1977, 2, 2, 131. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (B) | 33623 | bromo(methyl)magnesium | 75-16-1 | CH3BrMg | 详情 | 详情 |
| (I) | 33619 | (8S,13R,14S)-13-ethyl-7,8,13,14,15,16-hexahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H22O2 | 详情 | 详情 | |
| (II) | 33620 | C21H26O3 | 详情 | 详情 | ||
| (III) | 33621 | C23H28O3 | 详情 | 详情 | ||
| (IV) | 33622 | (8S,11S,13S,14S,17R)-13-ethyl-17-ethynyl-11,17-dihydroxy-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26O3 | 详情 | 详情 | |
| (C) | 23634 | acetylene | 74-86-2 | C2H2 | 详情 | 详情 |
合成路线3
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 |