Emivirine, MKC-442, Coactinon, -Drug Synthesis Database

【结构式】

【药物名称】Emivirine, MKC-442, Coactinon

【化学名称】6-Benzyl-1-(ethoxymethyl)-5-isopropyluracil
　　　　　　6-Benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione

【CA登记号】149950-60-7

【分子式】C₁₇H₂₂N₂O₃

【分子量】302.37649

【开发单位】Mitsubishi Chemical (Originator), Abbott (Licensee), Gilead (Licensee), Catalytica Pharmaceuticals (Bulk Supplier)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The reaction of the silylated 5-isopropylpyrimidine (I) with chloromethyl ethyl ether (II) by means of KI in dichloromethane gives 1-(ethoxymethyl)-5-isopropyl-2-thiouracil (III), which is condensed with benzaldehyde (IV) by means of lithium diisopropylamide (LDA) in THF, and desulfurized by reaction with H2O2 and NaOH in water to afford 1-(ethoxymethyl)-5-isopropyl-6-(alpha-hydroxybenzyl)uracil (V). The reaction of (V) with acetic anhydride and pyridine gives the acetate (VI), which is finally submitted to hydrogenolysis with H2 over Pd/C in acetic acid/water/dioxane.

参考文献中间体

【1】 Walker, R.T.; Baba, M.; De Clerq, E.; Takashima, H.; Inouye, N.; Ubasawa, M.; Miyasaka, T.; Sekiya, K.; Shigeta, S.; Tanaka, H.; Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. J Med Chem 1995, 38, 15, 2860.
【2】 Ubasawa, M.; Tanaka, H.; Walker, R.T.; Yuasa, S.; Miyasaka, T.; De Clerq, E.; Baba, M.; HEPT derivatives: 6-benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442). Nucleosides Nucleotides 1995, 14, 3-5, 575.

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)	27025	5-isopropyl-4-[(trimethylsilyl)methyl]-2-[(trimethylsilyl)sulfanyl]pyrimidine		C₁₄H₂₈N₂SSi₂	详情	详情
(II)	13149	1-(Chloromethoxy)ethane; Chloromethyl ethyl ether	3188-13-4	C₃H₇ClO	详情	详情
(III)	27026	1-(ethoxymethyl)-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone		C₁₀H₁₆N₂O₂S	详情	详情
(IV)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(V)	27027	1-(ethoxymethyl)-6-[hydroxy(phenyl)methyl]-5-isopropyl-2,4(1H,3H)-pyrimidinedione		C₁₇H₂₂N₂O₄	详情	详情
(VI)	27028	[3-(ethoxymethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl](phenyl)methyl acetate		C₁₉H₂₄N₂O₅	详情	详情

合成路线2

The reaction of 5-isopropyluracil (VII) with chloromethyl ethyl ether (II) by means of bis(trimethylsilyl)acetamide (BSA) and tetrabutylammonium iodide (TBI) in dichloromethane gives 1-(ethoxy-methyl)-5-isopropyluracil (VIII)(3), which is then condensed with benzaldehyde (IV) by means of LDA in THF to afford 1-(ethoxymethyl)-5-isopropyl-6-(alpha-hydroxybenzyl)uracil (V), already obtained.

参考文献中间体

【1】 Ubasawa, M.; Yuasa, S. (Mitsubishi Chemical Corp.); Antiviral combinations of 2',3'-dideoxyribonucleosides with 6-benzyl-1-ethoxymethyl-5-substd. uracil derivs.. EP 0631783; JP 1995097324 .
【2】 Ubasawa, M.; et al. (Mitsubishi Chemical Corp.); Production of 6-aralkyl substituted pyrimidine derivative. JP 1996003143 .

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)	27029	trimethylsilyl 4-[(trimethylsilyl)methyl]-2-pyrimidinyl sulfide		C₁₁H₂₂N₂SSi₂	详情	详情
(II)	13149	1-(Chloromethoxy)ethane; Chloromethyl ethyl ether	3188-13-4	C₃H₇ClO	详情	详情
(IV)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(V)	27027	1-(ethoxymethyl)-6-[hydroxy(phenyl)methyl]-5-isopropyl-2,4(1H,3H)-pyrimidinedione		C₁₇H₂₂N₂O₄	详情	详情
(VI)	27028	[3-(ethoxymethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl](phenyl)methyl acetate		C₁₉H₂₄N₂O₅	详情	详情
(VII)	27030	5-isopropyl-2,4(1H,3H)-pyrimidinedione		C₇H₁₀N₂O₂	详情	详情
(VIII)	27031	1-(ethoxymethyl)-5-isopropyl-2,4(1H,3H)-pyrimidinedione		C₁₀H₁₆N₂O₃	详情	详情

合成路线3

The condensation of ethyl 2-bromo-3-methylbutyrate (IX) with phenylacetonitrile (X) by means of activated Zn in THF gives the ethyl 2-isopropyl-3-oxo-4-phenylbutyrate (XI), which is cyclized with thiourea (XII) by means of sodium ethoxide in refluxing ethanol yielding 6-benzyl-5-isopropyl-2-thioracil (XIII). The desulfurization of (XIII) with a refluxing solution of 10% chloroacetic acid in water affords the corresponding uracil (XIV), which is finally alkylated with chloromethyl ethyl ether (II) and BSA in chloroform.

参考文献中间体

【1】 Larsen, D.K.; et al.; Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J Med Chem 1996, 39, 12, 2427.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	13149	1-(Chloromethoxy)ethane; Chloromethyl ethyl ether	3188-13-4	C₃H₇ClO	详情	详情
(IX)	27032	2-Bromoisovalerianic acid ethyl ester; ethyl 2-bromo-3-methylbutanoate	609-12-1	C₇H₁₃BrO₂	详情	详情
(X)	17046	Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide	140-29-4	C₈H₇N	详情	详情
(XI)	27033	ethyl 2-isopropyl-3-oxo-4-phenylbutanoate		C₁₅H₂₀O₃	详情	详情
(XII)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(XIII)	27034	6-benzyl-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone		C₁₄H₁₆N₂OS	详情	详情
(XIV)	27035	6-benzyl-5-isopropyl-2,4(1H,3H)-pyrimidinedione		C₁₄H₁₆N₂O₂	详情	详情

Extended Information