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【结 构 式】

【药物名称】FR-193108

【化学名称】(+)-N-[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-yl]-N'-[3-(1H-tetrazol-5-yl)phenyl]urea

【CA登记号】

【 分 子 式 】C34H34FN9O3

【 分 子 量 】635.70698

【开发单位】Fujisawa (Originator)

【药理作用】GASTROINTESTINAL DRUGS, Pancreatic Disorders, Treatment of, CCK1 (CCKA) Antagonists, CCK2 (CCKB/Gastrin) Antagonists

合成路线1

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
Extended Information