GSK-1120212B;JTP-74057;Trametinib Dimethyl Sulfoxide, -Drug Synthesis Database

【结构式】

【药物名称】GSK-1120212B;JTP-74057;Trametinib Dimethyl Sulfoxide

【化学名称】N-[3-[3-Cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,6,7-hexahydropyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide dimethyl sulfoxide solvate

【CA登记号】1187431-43-1;871700-17-3 (free base);871702-06-6 (sodium salt);871702-07-7 (monoacetate salt)

【分子式】C₂₆H₂₃FIN₅O₄.C₂H₆OS

【分子量】693.528

【开发单位】Japan Tobacco, Inc. (JP); licensed to GlaxoSmithKline (UK)

【药理作用】MAP Kinase Kinase 1 and 2 (MEK 1/2) Inhibitor;Oncolytic

合成路线1 合成路线2

合成路线1

Uracil intermediate (I) is obtained as follows. Condensation of 2-fluoro-4-iodophenyl isocyanate (XIII) with cyclopropylamine (XIV) in Et2O , or alternatively reaction of 2-fluoro-4-iodoaniline (XV) with CDI in the presence of Et3N in DMF, followed by condensation with cyclopropylamine (XIV) affords disubstituted urea (XVI). Cyclization of urea (XVI) is treated with malonic acid (XVII) in the presence of AcCl in Ac2O at 60 °C affords the pyrimidine trione (XVIII), which is chlorinated using POCl3 in the presence of PhNMe2 and a catalytic amount of H2O at 90 °C to provide a mixture of 6-chloropyrimidine (XIX) and the corresponding regioisomer. Finally, chloropyrimidine (XIX) is treated with methylamine (XX) in EtOH at 80 °C .
In an alternative procedure, acylation of urea (XVI) with cyanoacetic acid (XXI) by means of MsCl in DMF yields the N-(cyanoacetyl)urea (XXII), which cyclizes in aqueous NaOH at 80 °C to yield the amino-pyrimidine derivative (XXIII). Condensation of amine (XXIII) with dimethylformamide dimethylacetal (XXIV) in DMF affords formamidine (XXV), which is finally reduced using NaBH4 in EtOH/t-BuOH .

参考文献中间体

【2】 Sakai, T., Kawasaki, H., Abe, H. et al. (Japan Tobacco, Inc.). 5-Amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer. CN 101912400, EP 1761528, EP 1894932, EP 2298768, JP 2008201788, JP 2008501631, US 2006014768, US 7378423, US 2008312228, US 201024013, WO 2005121142.
【1】 Abe, H., Kikuchi, S., Hayakawa, K. et al. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-7407 DMSO solvate). ACS Med Chem Lett 2011, 2(4): 320.

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)	68359	1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil;3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-(methylamino)pyrimidine-2,4(1H,3H)-dione		C₁₄H₁₃FIN₃O₂	详情	详情
(XIII)	68369	2-fluoro-4-iodophenyl isocyanate		C₇H₃FINO	详情	详情
(XIV)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(XV)	63342	2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine	29632-74-4	C₆H₅FIN	详情	详情
(XVI)	68370	1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea		C₁₀H₁₀FIN₂O	详情	详情
(XVII)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(XVIII)	68371	1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione		C₁₃H₁₀FIN₂O₃	详情	详情
(XIX)	68372	6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione		C₁₃H₉ClFIN₂O₂	详情	详情
(XX)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(XXI)	12591	Cyanoacetic Acid; 2-Cyanoacetic acid	372-09-8	C₃H₃NO₂	详情	详情
(XXII)	68373	2-cyano-N-cyclopropyl-N-((2-fluoro-4-iodophenyl)carbamoyl)acetamide		C₁₃H₁₁FIN₃O₂	详情	详情
(XXIII)	68374	6-amino-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione		C₁₃H₁₁FIN₃O₂	详情	详情
(XXIV)	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
(XXV)	68375	(E)-N'-(1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide		C₁₆H₁₆FIN₄O₂	详情	详情

合成路线2

Cyclization of 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil (I) (optionally containing some 1-cyclopropyl regioisomer) with either diethyl 2-methylmalonate (II) in Ph2O at 220 °C or with 2-methylmalonic acid (III) in Ac2O at 100 °C yields the 5-hydroxypyrido[2,3-d]pyrimidine-2,4,7-trione derivative (IV) , which can be separated from its regioisomeric byproduct by crystallization from acetone . Treatment of compound (IV) with Tf2O in the presence of 2,6-lutidine in CHCl3 gives the corresponding triflate (V) . Similarly, reaction of (IV) with p-TsCl in the presence of Et3N and Me3N·HCl in acetonitrile produces tosylate (VI) . The condensation of triflate (V) with 3-nitroaniline (VII) at 130 °C furnishes the 5-(arylamino)pyrido[2,3-d]pyrimidine derivative (VIII), which undergoes rearrangement to the isomeric pyrido[4,3-d]pyrimidine (IX) in the presence of K2CO3 in MeOH/THF at 80 °C. Reduction of nitro compound (IX) by means of Na2S2O4 in DMF/H2O at 90 °C, followed by acetylation of the resulting amine with Ac2O in pyridine/CHCl3, leads to trametinib (X). Finally, crystallization of (X) from DMSO produces trametinib dimethyl sulfoxide solvate .
In an alternative procedure, condensation of either triflate (V) or tosylate (VI) with N-(3-aminophenyl)acetamide (XI) by means of 2,6-lutidine in DMA at 130 °C affords intermediate (XII), which upon rearrangement in the presence of NaOMe in THF/MeOH gives rise to the pyrido[4,3-d]pyrimidine compound (IX) .

参考文献中间体

【1】 Abe, H., Kikuchi, S., Hayakawa, K. et al. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-7407 DMSO solvate). ACS Med Chem Lett 2011, 2(4): 320.
【2】 Sakai, T., Kawasaki, H., Abe, H. et al. (Japan Tobacco, Inc.). 5-Amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer. CN 101912400, EP 1761528, EP 1894932, EP 2298768, JP 2008201788, JP 2008501631, US 2006014768, US 7378423, US 2008312228, US 201024013, WO 2005121142.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	68368	N-(3-aminophenyl)acetamide；3'-Aminoacetanilide		C₈H₁₀N₂O	详情	详情
(I)	68359	1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil;3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-(methylamino)pyrimidine-2,4(1H,3H)-dione		C₁₄H₁₃FIN₃O₂	详情	详情
(II)	30310	diethyl 2-methylmalonate	609-08-5	C₈H₁₄O₄	详情	详情
(III)	68360	2-methylmalonic acid	516-05-2	C₄H₆O₄	详情	详情
(IV)	68361	3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione		C₁₈H₁₅FIN₃O₄	详情	详情
(V)	68362	3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate		C₁₉H₁₄F₄IN₃O₆S	详情	详情
(VI)	68363	3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate		C₂₅H₂₁FIN₃O₆S	详情	详情
(VII)	57781	1-Amino-3-Nitrobenzene; 3-Nitroaniline; m-Nitroaniline	99-09-2	C₆H₆N₂O₂	详情	详情
(VIII)	68364	3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-5-((3-nitrophenyl)amino)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione		C₂₄H₁₉FIN₅O₅	详情	详情
(IX)	68365	3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-nitrophenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione		C₂₄H₁₉FIN₅O₅	详情	详情
(X)	68366	N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide		C₂₆H₂₃FIN₅O₄	详情	详情
(XII)	68367	N-(3-((3-cyclopropyl-1-(3-fluoro-5-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)acetamide		C₂₆H₂₃FIN₅O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)