【结 构 式】 |
【分子编号】41204 【品名】2-[5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1H-isoindole-1,3(2H)-dione 【CA登记号】 |
【 分 子 式 】C24H16FN3O3 【 分 子 量 】413.4078632 【元素组成】C 69.73% H 3.9% F 4.6% N 10.16% O 11.61% |
合成路线1
该中间体在本合成路线中的序号:(IX)The condensation of 2-methylaniline (I) with 2-fluorobenzonitrile (II) by means of BCl3 and AlCl3 gives 2-amino-2'-fluoro-3-methylbenzophenone (III), which is acylated at the amino group with bromoacetyl bromide (IV) in pyridine yielding the bromoacetamide (V). The cyclization of (V) with hydroxylamine and NaOH affords the benzodiazepinone-N-oxide (VI), which is treated with acetic anhydride to provide 3-acetoxy-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (VII). The reaction of (VII) with potassium phthalimide (VIII) and NaI gives the phthalimido derivative (IX), which by cleavage with hydrazine yields 3-amino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (X). The protection of the amino group of (X) with Boc2O and TEA affords the carbamate (XI), which is alkylated with ethyl bromoacetate (XII) by means of NaH giving the ethoxycarbonylmethyl derivative (XIII). The hydrolysis of (XIII) with NaOH affords the corresponding carboxymethyl derivative (XIV), which is condensed with 3-azabicyclo[3,2,2]nonane (XV) by means of HOBT, WSCD and TEA to give the expected amide (XVI). The cleavage of the tert-butoxycarbonyl group of (XVI) with HCl yields the amine (XVII), which is finally condensed with the activated carbamate (XVIII) to furnish the title compound.
【1】 Toyoda, T.; Adachi, M.; Sugasawa, T.; et al.; Aminohaloborane in organic synthesis. I. Specific ortho substitution reaction of anilines. J Am Chem Soc 1978, 100, 4842. |
【2】 Satoh, Y.; Tabuchi, S.; Mitsui, H.; Design of dual CCK-A and CCK-B receptor antagonists. Drugs Fut 1997, 22, 10, 1117. |
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) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline;2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
(II) | 41199 | 2-fluorobenzonitrile | 394-47-8 | C7H4FN | 详情 | 详情 |
(III) | 41200 | (2-amino-3-methylphenyl)(2-fluorophenyl)methanone | C14H12FNO | 详情 | 详情 | |
(IV) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
(V) | 41201 | 2-bromo-N-[2-(2-fluorobenzoyl)-6-methylphenyl]acetamide | C16H13BrFNO2 | 详情 | 详情 | |
(VI) | 41202 | 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate | C16H13FN2O2 | 详情 | 详情 | |
(VII) | 41203 | 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl acetate | C18H15FN2O3 | 详情 | 详情 | |
(VIII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
(IX) | 41204 | 2-[5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1H-isoindole-1,3(2H)-dione | C24H16FN3O3 | 详情 | 详情 | |
(X) | 41205 | 3-amino-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C16H14FN3O | 详情 | 详情 | |
(XI) | 41206 | tert-butyl 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate | C21H22FN3O3 | 详情 | 详情 | |
(XII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
(XIII) | 41207 | ethyl 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetate | C25H28FN3O5 | 详情 | 详情 | |
(XIV) | 41208 | 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetic acid | C23H24FN3O5 | 详情 | 详情 | |
(XV) | 41209 | 3-azabicyclo[3.2.2]nonane | C8H15N | 详情 | 详情 | |
(XVI) | 41210 | tert-butyl 1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate | C31H37FN4O4 | 详情 | 详情 | |
(XVII) | 41211 | 3-amino-1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C26H29FN4O2 | 详情 | 详情 | |
(XVIII) | 41212 | 4-nitrophenyl 3-(1H-1,2,3,4-tetraazol-5-yl)phenylcarbamate | C14H10N6O4 | 详情 | 详情 |