-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-(6-Amino-2-methylpyridin-3-ylmethyl)-2-[2-(cyclopropylmethyl)-7-methyl-1,1,5-trioxo-3,4,5,6-tetrahydro-2H-pyrido[3,4-e][1,2,4]thiadiazin-6-yl]acetamide

【CA登记号】262616-78-4, 262616-79-5 (trifluoroacetate)

【分子式】C₂₀H₂₆N₆O₄S

【分子量】446.53202

【开发单位】Merck & Co. (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors

合成路线1 合成路线2

合成路线1

4-Hydroxy-6-methyl-3-nitropyridone (I) is chlorinated to (II) by treatment with POCl3 in the presence of benzyltriethylammonium chloride. Alkylation of pyridone (II) with ethyl bromoacetate (III) and NaH leads to the pyridoneacetate (IV) (1). Displacement of the chloride group of (IV) with 2-mercaptobenzothiazole (V) affords the thioether (VI). After reduction of the nitro group of (VI) by catalytic hydrogenation, the resultant amine (VII) is protected as the di-Boc derivative (VIII) with di-tert-butyl dicarbonate and DMAP. Oxidation of the thioether (VIII) with KmnO4 gives the sulfone (IX), which is submitted to reductive cleavage with Zn/AcOH. Finally chlorination of the intermediate zinc sulfinate with NCS furnishes the sulfonyl chloride (X) (1,2).

参考文献中间体

【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
(I)	23337	4-hydroxy-6-methyl-3-nitro-2(1H)-pyridinone	4966-90-9	C₆H₆N₂O₄	详情	详情
(II)	23339	4-chloro-6-methyl-3-nitro-2(1H)-pyridinone		C₆H₅ClN₂O₃	详情	详情
(III)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(IV)	64710	ethyl 2-[4-chloro-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate		C₁₀H₁₁ClN₂O₅	详情	详情
(V)	24677	1,3-benzothiazol-2-ylhydrosulfide	149-30-4	C₇H₅NS₂	详情	详情
(VI)	64711	ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate		C₁₇H₁₅N₃O₅S₂	详情	详情
(VII)	64712	ethyl 2-[3-amino-4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₁₇H₁₇N₃O₃S₂	详情	详情
(VIII)	64713	ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₂₇H₃₃N₃O₇S₂	详情	详情
(IX)	64714	ethyl 2-[4-(1,3-benzothiazol-2-ylsulfonyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₂₇H₃₃N₃O₉S₂	详情	详情
(X)	64715	ethyl 2-[3-[bis(tert-butoxycarbonyl)amino]-4-(chlorosulfonyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₂₀H₂₉ClN₂O₉S	详情	详情

合成路线2

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)

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)