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【结 构 式】 
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【分子编号】12416 【品名】methyl 4-amino-2-methoxybenzoate 【CA登记号】27492-84-8 |
【 分 子 式 】C9H11NO3 【 分 子 量 】181.19128 【元素组成】C 59.66% H 6.12% N 7.73% O 26.49% |
合成路线1
该中间体在本合成路线中的序号：(I)The nitration of methyl 2-methoxy-4-aminobenzoate (I) with nitric acid in acetic acid-acetic anhydride, followed by hydrolysis with methanolic H2SO4 gives methyl 2-methoxy-4-amino-5-nitrobenzoate (II), which is reduced with H2 over Raney-Ni in methanol to yield methyl-2-methoxy-4,5-diaminohenzoate (III). The cyclization of (III) with NaNO2 in aqueous HCl affords methyl 6-methoxybenzotriazole-5-carboxylate (IV), which is finally condensed with 1-allylpyrrolidin-2-ylmethylamine (V) in refluxing toluene.
| 【1】 Leeson, P.A.; Serradell, M.N.; Castaner, J.; Blancafort, P.; Mealy, N.E.; Alizapride. Drugs Fut 1981, 6, 1, 11. |
| 【2】 Bulteau, G.; Acher, J.; Collignon, C.; Monier, J.-C. (Societe d'Etudes Scientifiques et Industrielles de L'Ile de France); N-(1'-allypyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimido benzamide and its pharmaceutically acceptable salts. US 4039672 . |
| 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) | 12416 | methyl 4-amino-2-methoxybenzoate | 27492-84-8 | C9H11NO3 | 详情 | 详情 |
| (II) | 32212 | methyl 4-amino-2-methoxy-5-nitrobenzoate | C9H10N2O5 | 详情 | 详情 | |
| (III) | 32213 | methyl 4,5-diamino-2-methoxybenzoate | C9H12N2O3 | 详情 | 详情 | |
| (IV) | 32214 | methyl 6-methoxy-1H-1,2,3-benzotriazole-5-carboxylate | C9H9N3O3 | 详情 | 详情 | |
| (V) | 32211 | (1-allyl-2-pyrrolidinyl)methanamine; (1-allyl-2-pyrrolidinyl)methylamine | 66411-51-6 | C8H16N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)A new synthesis for [14C]-labeled batanopride has been described: The starting material is 4-amino-2-hydroxybenzoic acid labeled with [14C] at the carboxy group (I). The methylation of (I) in the usual way gives 4-amino-2-methoxybenzoic acid methyl ester (II), which is treated with acetic anhydride to yield the corresponding acetamido derivative (III). Chlorination of (III) with Cl2 in acetic acid affords 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester (IV), which is hydrolyzed with aqueous NaOH to 4-amino-5-chloro-2-methoxybenzoic acid (V). The condensation of (V) with 2-(diethylamino)ethylamine (VI) by means of triethylamine and isobutyl chloroformate in THF gives the corresponding amide (VII), which is demethylated with sodium ethanethiolate in DMF to yield the phenolate (VIII). The condensation of (VIII) with 3-chloro-2-butanone (IX) in DMF affords batanopride free base (X), which is finally treated with HCl in acetone - water.
| 【1】 Standridge, R.T.; Swigor, J.E.; Synthesis of 4-amino-5-chloro-N[2-(diethylamino)ethyl]-2-[(butan-2-on-3-yl)oxy]-[carbonyl-C-14]benzamide hydrochloride (C-14-batanopride). J Label Compd Radiopharm 1991, 29, 9, 983. |
| 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) | 12415 | 4-Aminosalicylic Acid; 4-Amino-2-hydroxybenzoic acid | 65-49-6 | C7H7NO3 | 详情 | 详情 |
| (I) | 45126 | 4-amino-2-hydroxybenzoic acid | C7H7NO3 | 详情 | 详情 | |
| (II) | 12416 | methyl 4-amino-2-methoxybenzoate | 27492-84-8 | C9H11NO3 | 详情 | 详情 |
| (II) | 45127 | methyl 4-amino-2-methoxybenzoate | C9H11NO3 | 详情 | 详情 | |
| (III) | 12417 | methyl 4-(acetamido)-2-methoxybenzoate; Methyl 4-acetamido-2-methoxybenzoate | 4093-28-1 | C11H13NO4 | 详情 | 详情 |
| (III) | 45128 | methyl 4-(acetamido)-2-methoxybenzoate | C11H13NO4 | 详情 | 详情 | |
| (IV) | 12418 | 4-Acetamido-5-chloro-2-methoxy methyl benzoate; methyl 4-(acetamido)-5-chloro-2-methoxybenzoate; Methyl 4-acetamido-5-chloro-2-methoxybenzoate; 4-Acetamido-5-chloro-2-methoxybenzoic acid methyl ester; 4-Acetamido-5-chloro-o-anisic acid methyl ester | 4093-31-6 | C11H12ClNO4 | 详情 | 详情 |
| (IV) | 45129 | methyl 4-(acetamido)-5-chloro-2-methoxybenzoate | C11H12ClNO4 | 详情 | 详情 | |
| (V) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (V) | 45130 | 4-amino-5-chloro-2-methoxybenzoic acid | C8H8ClNO3 | 详情 | 详情 | |
| (VI) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (VII) | 12421 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | 364-62-5 | C14H22ClN3O2 | 详情 | 详情 |
| (VII) | 45131 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | C14H22ClN3O2 | 详情 | 详情 | |
| (VIII) | 12422 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (VIII) | 45132 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (IX) | 12423 | 3-Chloro-2-butanone | 4091-39-8 | C4H7ClO | 详情 | 详情 |
| (X) | 12424 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 | |
| (X) | 45133 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Condensation of the ortho-metalated derivative of 3-fluoroanisole (I) –generated in situ by treatment of anisole (I) with BuLi in THF at –78 °C– with 6-chloro-2-phenyl-3,1-benzoxazin-4-one (II) gives the diaryl ketone (III), which is N-deprotected by means of KOH in refluxing MeOH/H2O, yielding the aniline derivative (IV). Diazotization of amine (IV) with NaNO2 and HCl in AcOH/H2O, followed by treatment with I2 in the presence of KI in cold EtOAc/H2O affords the aryl iodide (V). Iodobenzophenone (V) is then subjected to Heck coupling with N-Boc-propargylamine (VI) in the presence of PdCl2(PPh3)2, CuI and Et2NH in CH2Cl2 to provide adduct (VII), which is submitted sequentially to triple bond hydration, N-Boc deprotection and cyclization by sequential treatment with HgSO4 and formic acid in CH2Cl2 at 0 °C, and then DIEA in CH2Cl2 or by treatment with HCl in dioxane/H2O and then Na2CO3 in CH2Cl2 to give the 3,4-dihydro[2]benzoazepinone (VIII). Condensation of benzazepinone (VIII) with N,Ndimethylformamide dimethylacetal (IX) in toluene at 80 °C yields the 4-(dimethylaminomethylene)[2]benzoazepinone derivative (X) , which is finally condensed with methyl 4-guanidino-2-methoxybenzoate hydrochloride (XI) in the presence of K2CO3 in refluxing MeOH .
Intermediate (XI) is prepared by condensation of methyl 4-amino-2-methoxybenzoate (XII) with chloroformamidine hydrochloride (XIII) in Me2SO2 at 120 °C, followed by acidification with TFA to yield methyl 4-guanidino-2-methoxybenzoate trifluoroacetate salt (XIV). Subsequent treatment of the trifluoroacetate salt with HCl at 80 °C provides the corresponding hydrochloride (XIV) .
| 【1】 Claiborne, C.F., Payne, L.J., Boyce, R.J. et al. (Millennium Pharmaceuticals, Inc.). Compounds and methods for inhibiting mitotic progression by inhibition of Aurora kinase. EP 1771450, EP 1905773, JP 200753768, JP 2008285484, US 200525602, US 7572784, WO 2005111039. |
| 【2】 Claiborne, C.F., Sells, T.B., Stroud, S.G. (Millennium Pharmaceuticals, Inc.). Compounds for inhibiting mitotic progression. EP 2086981, JP 2010510215, US 2008167292, WO 2008963525. |
| 【3】 Sugiki, M., Sagi, K., Fujita, K., Kayahara, T., Takehana, S., Sakurai, K., Tashiro, K., (Ajinomoto Co., Inc.). Amidinophenylpyruvic acid derivative. US 2003109547, US 6710056, WO 2001042199. |
| 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) | 69123 | 1-fluoro-3-methoxybenzene；3-Fluoroanisole;m-Fluoroanisole | 456-49-5 | C7H7FO | 详情 | 详情 |
| (II) | 69124 | 6-chloro-2-phenyl-3,1-benzoxazin-4-one;6-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one | C14H8ClNO2 | 详情 | 详情 | |
| (III) | 69125 | (2-(benzylamino)-5-chlorophenyl)(2-fluoro-6-methoxyphenyl)methanone | C21H17ClFNO2 | 详情 | 详情 | |
| (IV) | 69126 | (2-amino-5-chlorophenyl)(2-fluoro-6-methoxyphenyl)methanone | C14H11ClFNO2 | 详情 | 详情 | |
| (V) | 69127 | (5-chloro-2-iodophenyl)(2-fluoro-6-methoxyphenyl)methanone | C14H9ClFIO2 | 详情 | 详情 | |
| (VI) | 69128 | tert-butyl prop-2-yn-1-ylcarbamate;tert-butyl prop-2-yn-1-ylcarbamate;N-Boc-propargylamine;N-(tert-Butoxycarbonyl)propargyl amine | 92136-39-5 | C8H13NO2 | 详情 | 详情 |
| (VII) | 69129 | tert-butyl (3-(4-chloro-2-(2-fluoro-6-methoxybenzoyl)phenyl)prop-2-yn-1-yl)carbamate | C22H21ClFNO4 | 详情 | 详情 | |
| (VIII) | 69130 | 8-chloro-1-(2-fluoro-6-methoxyphenyl)-3H-benzo[c]azepin-5(4H)-one | C17H13ClFNO2 | 详情 | 详情 | |
| (IX) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (X) | 69131 | (Z)-8-chloro-4-((dimethylamino)methylene)-1-(2-fluoro-6-methoxyphenyl)-3H-benzo[c]azepin-5(4H)-one | C20H18ClFN2O2 | 详情 | 详情 | |
| (XI) | 69132 | 4-guanidino-2-methoxybenzoic acid hydrochloride | 342908-52-5 | C9H11N3O3.HCl | 详情 | 详情 |
| (XII) | 12416 | methyl 4-amino-2-methoxybenzoate | 27492-84-8 | C9H11NO3 | 详情 | 详情 |
| (XIII) | 69133 | chloroformamidine hydrochloride;carbamimidic chloride hydrochloride | CH3ClN2.HCl | 详情 | 详情 | |
| (XIV) | 69134 | methyl 4-guanidino-2-methoxybenzoate trifluoroacetate salt;methyl 4-guanidino-2-methoxybenzoate 2,2,2-trifluoroacetate | C10H13N3O3.C2HF3O2 | 详情 | 详情 |