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【结 构 式】 
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【分子编号】10279 【品名】(2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone 【CA登记号】719-59-5 |
【 分 子 式 】C13H10ClNO 【 分 子 量 】231.68124 【元素组成】C 67.4% H 4.35% Cl 15.3% N 6.05% O 6.91% |
合成路线1
该中间体在本合成路线中的序号：(II)A new synthesis of adinazolam has been described: The condensation of phthaloyl-glycyl chloride (I) with 2-amino-5-chlorobenzophenone (II) in refluxing toluene gives 4-chloro-2-(phthaloylglycylamido)benzophenone (III), which is cyclized by means of hydrazine in refluxing ethanol yielding 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (IV). The reaction of (IV) with P2S5 in hot pyridine affords the corresponding thione (V), which is finally cyclized with N,N-dimethylglycine hydrazide by means of triethylamine in refluxing butanol. The starting products (I) and (II) are obtained as follows: The reaction of N-(ethoxycarbonyl)phthalimide (VI) with glycine by means of Na2CO3 in water gives the N-phthaloylglycine (VII), which is then treated with refluxing SOCl2 to give (I). The protection of 2-amino-4-chlorobenzoic acid (VIII) with tosyl chloride gives the corresponding N-tosyl derivative (IX), which by reaction with refluxing SOCl2 is converted into the acyl chloride (X). Finally, this compound is submitted to a Friedel-Craft's condensation with benzene and AlCl3 to afford (II).
| 【1】 Johnson, T.D.; Hsi, R.S.P.; Carbon-14 labeled 1,4-benzodiazepines. 3. J Label Compd Radiopharm 1976, 12, 4, 613-619. |
| 【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87. |
| 【3】 Stelzer, L.S.; Hsi, R.S.P.; Synthesis of adinazolam mesylate-multiply labeled with carbon-13 and deuterium. J Label Compd Radiopharm 1989, 26, 3, 287. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 | |
| 40924 | 2-(dimethylamino)acetohydrazide | 539-64-0 | C4H11N3O | 详情 | 详情 | |
| (I) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (II) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (III) | 10280 | N-(2-Benzoyl-4-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide | C23H15ClN2O4 | 详情 | 详情 | |
| (IV) | 10281 | 7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,4-benzdiazepin-2-one-5-phenyl-7-chloro | 1088-11-5 | C15H11ClN2O | 详情 | 详情 |
| (V) | 10282 | 7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2-ylhydrosulfide; 7-Chloro-5-phenyl-3H-1,4-benzodiazepine-2-thiol | C15H11ClN2S | 详情 | 详情 | |
| (VI) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (VII) | 10284 | N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid | 4702-13-0 | C10H7NO4 | 详情 | 详情 |
| (VIII) | 10285 | 2-Amino-5-chlorobenzoic acid | 635-21-2 | C7H6ClNO2 | 详情 | 详情 |
| (IX) | 10286 | 5-Chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoic acid | C14H12ClNO4S | 详情 | 详情 | |
| (X) | 10287 | 5-Chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoyl chloride | C14H11Cl2NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 2-amino-5-chlorobenzophenone (I) with formic acid gives 2-formylamino-5-chlorobenzophenone (II), which by cyclization with hydrazine in ethanol is converted into 3-amino-6-chloro-4-hydroxy-4-phenyl-3,4-dihydroquinazoline (III). The reaction of (III) with formic acid in acetic anhydride - acetic acid yields 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone (IV), which by reaction with formaldehyde in refluxing xylene affords 5-chloro-2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone (V). The reaction of (V) with phthalimide (VI), triethylphosphine and diethyl azodicarboxylate in THF gives 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (VII), which is cyclized with hydrazine in hot ethanol to 8-chloro-1-(aminomethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (VIII). Finally, this compound is methylated with formaldehyde and sodium cyanoborohydride in acetonitrile - acetic acid.
| 【1】 Gall, M.; Hester, J.B.; US 3947466 . |
| 【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87. |
| 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) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (II) | 35936 | 2-benzoyl-4-chlorophenylformamide | C14H10ClNO2 | 详情 | 详情 | |
| (III) | 35937 | 3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol | C14H12ClN3O | 详情 | 详情 | |
| (IV) | 35938 | [5-chloro-2-(4H-1,2,4-triazol-4-yl)phenyl](phenyl)methanone | C15H10ClN3O | 详情 | 详情 | |
| (V) | 35939 | [2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]-5-chlorophenyl](phenyl)methanone | C17H14ClN3O3 | 详情 | 详情 | |
| (VI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (VII) | 35940 | 2-([4-(2-benzoyl-4-chlorophenyl)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4H-1,2,4-triazol-3-yl]methyl)-1H-isoindole-1,3(2H)-dione | C33H20ClN5O5 | 详情 | 详情 | |
| (VIII) | 35941 | (8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)methylamine; (8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)methanamine | C17H14ClN5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(I)1) The alkylation of 2-amino-5-chlorobenzophenone (I) with 2,2,2-trifluoroethyl trichloromethansulfonate (II) in refluxing xylene gives the N-trifluoroethyl derivative (III), which is then cyclized with glycine ethyl ester (A) in refluxing pyridine. 2) Compound (III) can also be bromoacetylated with bromoacetyl bromide (B) in refluxing benzene yielding the N-bromoacetyl compound (IV), which is then cyclized with ammonia in CHCl3. 3) By alkylation of 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IX) with NaOMe and 2,2,2-trifluoroethyl iodide in MeOH.
| 【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 . |
| 【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 . |
| 【3】 Topliss, J.G.; Verfahren zur Herstellung von neuen 1,4-benzodiazepinen bzw. ihren 4-Oxyden. CH 505842; DE 1793682; FR 1518382; GB 1179125 . |
| 【4】 Castaner, J.; Thorpe, P.; Halazepam. Drugs Fut 1978, 3, 2, 109. |
| 【5】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18806 | 1,1,1-trifluoro-2-iodoethane | 353-83-3 | C2H2F3I | 详情 | 详情 | |
| (A) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (B) | 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) | 33474 | 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate | 23199-56-6 | C3H2Cl3F3O3S | 详情 | 详情 |
| (III) | 33848 | [5-chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](phenyl)methanone | C15H11ClF3NO | 详情 | 详情 | |
| (IV) | 33849 | N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide | C17H12BrClF3NO2 | 详情 | 详情 | |
| (IX) | 10281 | 7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,4-benzdiazepin-2-one-5-phenyl-7-chloro | 1088-11-5 | C15H11ClN2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The starting benzophenone (I) can also be obtained in several different ways: a) By a Friedel-Crafts reaction of p-chloroaniline (X) and benzoyl chloride (D). b) By reaction of 5-chloroanthranilic acid (XI) with acetic anhydride to the bicyclic compound (XII), which is then submitted to a Grignard reaction with phenylmagnesium bromide (E). c) By oxidation of 2,3-diphenyl-5-chloroindole (XIII) with CrO3 to the N-benzoylbenzophenone (XIV), followed by debenzoylation with NaOH.
| 【1】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 . |
| 【2】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (E) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (I) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (X) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (XI) | 10285 | 2-Amino-5-chlorobenzoic acid | 635-21-2 | C7H6ClNO2 | 详情 | 详情 |
| (XII) | 33853 | 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one | C9H6ClNO2 | 详情 | 详情 | |
| (XIII) | 33854 | 5-chloro-2,3-diphenyl-1H-indole | C20H14ClN | 详情 | 详情 | |
| (XIV) | 33855 | N-(2-benzoyl-4-chlorophenyl)benzamide | C20H14ClNO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)This compound can be obtained by two related ways (1,2): 1) The Grignard reaction of 2-amino-5-chlorobenzophenone (I) with methylmagnesium iodide in ether gives 2-amino-5-chloromethylbenzhydrol (II), which by reaction with ethyl isothiocyanate (III) in ether yields 2-(omega-ethylthioureido)-5-chloro-alpha-methylbenzhydrol (IV). Finally this compound is treated with mercuric oxide in refluxing ethanol. 2) The reaction of (II) with ethyl isocyanate (V) in ether gives 2-(omega-ethylureido)-5-chloro-alpha-methylbenzhydrol (VI), which is finally cyclized by treatment with aqueous 48% HBr at 100 C.
| 【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Neuman, M.; Etifoxine hydrochloride. Drugs Fut 1981, 6, 9, 550. |
| 【2】 Kuch, H.; et al. (Farbwerke Hoechst A.G.); BE 707013; CA 870620; CH 502366; CH 522671; CH 532603; CH 532604; CH 534174; DE 1670772; FR 1571287; FR M7358; GB 1179856; GB 1197479; JP 7125385; JP 7126945; JP 7126946; JP 7126947; NL 6715652; US 3725404; ZA 6706887 . |
| 【3】 Hoffman, I.; et al.; 2-Ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1,benzoxazine, a new psychotropic compound. Arzneim-Forsch 1970, 20, 7, 975. |
| 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) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (II) | 60956 | 1-(2-amino-5-chlorophenyl)-1-phenyl-1-ethanol | C14H14ClNO | 详情 | 详情 | |
| (III) | 60959 | 1-isothiocyanatoethane; ethyl isothiocyanate | C3H5NS | 详情 | 详情 | |
| (IV) | 60958 | N-[4-chloro-2-(1-hydroxy-1-phenylethyl)phenyl]-N'-ethylthiourea | C17H19ClN2OS | 详情 | 详情 | |
| (V) | 28738 | ethyl isocyanate | 109-90-0 | C3H5NO | 详情 | 详情 |
| (VI) | 60957 | N-[4-chloro-2-(1-hydroxy-1-phenylethyl)phenyl]-N'-ethylurea | C17H19ClN2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The tosylation of 2-amino-5-chlorobenzophenone (I) with tosyl chloride (II) in pyridine gives 2-tosylamido-5-chlorobenzophenone (III), which is methylated with dimethyl sulfate and sodium methoxide in toluene yielding N-methyl-2-tosylamido-5-chlorobenzophenone (IV). Hydrolysis of (IV) with aqueous sulfuric acid affords 2-methylamino-5-chlorobenzophenone (V), which is acylated with bromoacetyl chloride (VI) in benzene to give N-methyl-2-(bromoacetylamido)-5-chlorobenzophenone (VII). Finally this compound is condensed with 2-methylallylamine (VIII) in acetone
| 【1】 Mouzin, G.; Cousse, H.; Stenger, A.; Casadio, S. (Pierre Fabre S.A.); US 4372975 . |
| 【2】 Serradell, M.N.; Castaner, J.; Souto, M.; Dinazafone. Drugs Fut 1984, 9, 7, 501. |
| 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) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (II) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (III) | 61085 | N-(2-benzoyl-4-chlorophenyl)(phenyl)methanesulfonamide | C20H16ClNO3S | 详情 | 详情 | |
| (IV) | 61086 | N-(2-benzoyl-4-chlorophenyl)-N-methylphenylmethanesulfonamide | C21H18ClNO3S | 详情 | 详情 | |
| (V) | 33972 | [5-chloro-2-(methylamino)phenyl](phenyl)methanone | 1022-13-5 | C14H12ClNO | 详情 | 详情 |
| (VI) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VII) | 33973 | N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-methylacetamide | C16H13BrClNO2 | 详情 | 详情 | |
| (VIII) | 61087 | 2-methyl-2-propen-1-amine; 2-methyl-2-propenylamine | C4H9N | 详情 | 详情 |