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【结 构 式】 
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【分子编号】18339 【品名】5-(aminomethyl)-6-methyl-2-pyridinamine; 5-(aminomethyl)-6-methyl-2-pyridinylamine 【CA登记号】 |
【 分 子 式 】C7H11N3 【 分 子 量 】137.18456 【元素组成】C 61.29% H 8.08% N 30.63% |
合成路线1
该中间体在本合成路线中的序号：(XI)Condensation of glycine benzyl ester (I) and acetaldehyde (II) in the presence of trimethylsilyl cyanide produced the aminonitrile (III), which was isolated as the hydrochloride salt. Further reaction of (III) with oxalyl chloride in o-dichlorobenzene at 100 C afforded the pyrazinone (IV). Subsequent, displacement of the 3-chloro group of (IV) by phenethylamine (V) in refluxing EtOAc gave the aminopyrazinone (VI). The benzyl ester group of (VI) was then hydrolyzed with LiOH in a mixture of H2O/MeOH/THF to yield acid (VII). Dechlorination of (VIII) by Raney-Ni alloy in the presence of NaOH provided pyrazinone (VIII). Reaction of 6-amino-3-bromo-2-methylpyridine (IX) with CuCN in boiling DMF gave nitrile (X), which was reduced to the primary amine (XI) by catalytic hydrogenation over Pd/C. Finally, acid (VIII) was coupled with amine (XI) using EDC and HOBt to furnish the corresponding amide, which was converted to the dihydrochloride salt.
| 【1】 Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates. J Med Chem 1998, 41, 23, 4466. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 18331 | benzyl 2-[(1-cyanoethyl)amino]acetate | C12H14N2O2 | 详情 | 详情 | |
| (IV) | 18332 | benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate | C14H12Cl2N2O3 | 详情 | 详情 | |
| (V) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (VI) | 18334 | benzyl 2-[3-chloro-2-methyl-6-oxo-5-(phenethylamino)-1(6H)-pyrazinyl]acetate | C22H22ClN3O3 | 详情 | 详情 | |
| (VII) | 18335 | 2-[3-chloro-2-methyl-6-oxo-5-(phenethylamino)-1(6H)-pyrazinyl]acetic acid | C15H16ClN3O3 | 详情 | 详情 | |
| (VIII) | 18336 | 2-[6-methyl-2-oxo-3-(phenethylamino)-1(2H)-pyrazinyl]acetic acid | C15H17N3O3 | 详情 | 详情 | |
| (IX) | 18337 | 5-bromo-6-methyl-2-pyridinamine; 5-bromo-6-methyl-2-pyridinylamine; 6-AMINO-3-BROMO-2-METHYLPYRIDINE | 42753-71-9 | C6H7BrN2 | 详情 | 详情 |
| (X) | 18338 | 6-amino-2-methylnicotinonitrile | C7H7N3 | 详情 | 详情 | |
| (XI) | 18339 | 5-(aminomethyl)-6-methyl-2-pyridinamine; 5-(aminomethyl)-6-methyl-2-pyridinylamine | C7H11N3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The acid chloride (X) is condensed with cyclopropylmethylamine (XI) to produce the sulfonamide (XII). Subsequent acidic Boc group cleavage in (XII) leads to the amine (XIII). Alkaline hydrolysis of the ethyl ester group of (XIII) provides the acid (XIV), which is subsequently coupled to 6-amino-3-(aminomethyl)-2-methylpyridine (XV) by means of EDC/HOAt to yield the amide (XVI). Finally, condensation of (XVI) with HCHO, followed by cyclization either in the presence of EDC or under acidic conditions, furnishes the target pyridothiadiazine. (1,2)
| 【1】 Sanderson, P.E.J.; Cutrona, K.J.; Savage, K.L.; Naylor-Olsen, A.M.; Bickel, D.J.; Bohn, D.L.; Clayton, F.C.; Krueger, J.A.; Lewis, S.D.; Lucas, B.J.; Lyle, E.A.; Wallace, A.A.; Welsh, D.C.; Yan, Y.; 3-Amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors. Bioorg Med Chem Lett 2003, 13, 8, 1441. |
| 【2】 Sanderson, P.E.; Cutrona, K. (Merck & Co., Inc.); Thrombin inhibitors. EP 1117660; JP 2002525370; US 6117888; WO 0018762 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 64715 | ethyl 2-[3-[bis(tert-butoxycarbonyl)amino]-4-(chlorosulfonyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C20H29ClN2O9S | 详情 | 详情 | |
| (XI) | 59524 | Aminomethylcyclopropane; Cyclopropanemethylamine | 2516-47-4 | C4H9N | 详情 | 详情 |
| (XII) | 64716 | ethyl 2-[3-[bis(tert-butoxycarbonyl)amino]-4-{[(cyclopropylmethyl)amino]sulfonyl}-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C24H37N3O9S | 详情 | 详情 | |
| (XIII) | 64717 | ethyl 2-[3-amino-4-{[(cyclopropylmethyl)amino]sulfonyl}-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C14H21N3O5S | 详情 | 详情 | |
| (XIV) | 64718 | 2-[3-amino-4-{[(cyclopropylmethyl)amino]sulfonyl}-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid | C12H17N3O5S | 详情 | 详情 | |
| (XV) | 18339 | 5-(aminomethyl)-6-methyl-2-pyridinamine; 5-(aminomethyl)-6-methyl-2-pyridinylamine | C7H11N3 | 详情 | 详情 | |
| (XVI) | 64719 | 2-[3-amino-4-{[(cyclopropylmethyl)amino]sulfonyl}-6-methyl-2-oxo-1(2H)-pyridinyl]-N-[(6-amino-2-methyl-3-pyridinyl)methyl]acetamide | C19H26N6O4S | 详情 | 详情 |