1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene -Drug Synthesis Database

【结构式】

【分子编号】28425

【品名】1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene

【CA登记号】

【分子式】C₁₀H₉ClF₃NO

【分子量】251.6355096

【元素组成】C 47.73% H 3.6% Cl 14.09% F 22.65% N 5.57% O 6.36%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

Silylated 4-oxoazetidine-2-carboxylic acid (I) was converted to the mixed anhydride with isobutyl chloroformate, and then reduced to alcohol (II) with NaBH4. Subsequent Mitsunobu coupling of (II) with mercaptotetrazole (III) provided thioether (IV). Desilylation of (IV) was then achieved by treatment with CsF in MeOH to give (V). Reaction of 4-(trifluoromethyl)benzyl chloride (VI) with methylamine afforded secondary amine (VII). This was reacted with phosgene and diisopropyl ethylamine to produce the carbamoyl chloride (VIII). Finally, condensation of this chloride with azetidinone (V) in the presence of lithium bis(trimethylsilyl)amide furnished the target urea.

参考文献中间体

合成目标

【1】 Yoakim, C.; Ogilvie, W.W.; Cameron, D.R.; Chabot, C.; Grand-Maitre, C.; Guse, I.; Hache, B.; Kawai, S.; Naud, J.; O'Meara, J.A.; Plante, R.; Deziel, R.; Potent beta-lactam inhibitors of human cytomegalovirus protease. Antivir Chem Chemother 1998, 9, 5, 379.

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)	28418	(2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid		C₁₀H₁₉NO₃Si	详情	详情
(II)	28419	(4R)-1-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-2-azetidinone		C₁₀H₂₁NO₂Si	详情	详情
(III)	28420	5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide	13183-79-4	C₂H₄N₄S	详情	详情
(IV)	28421	(4R)-1-[tert-butyl(dimethyl)silyl]-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone		C₁₂H₂₃N₅OSSi	详情	详情
(V)	28422	(4R)-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone		C₆H₉N₅OS	详情	详情
(VI)	28423	1-(chloromethyl)-4-(trifluoromethyl)benzene	939-99-1	C₈H₆ClF₃	详情	详情
(VII)	28424	N-methyl-N-[4-(trifluoromethyl)benzyl]amine		C₉H₁₀F₃N	详情	详情
(VIII)	28425	1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene		C₁₀H₉ClF₃NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Serine derivative (I) is converted into butyric acid derivative (II) by first treatment with isobutyl chloroformate and Et3N in THF, followed by reaction with ethereal diazomethane, Wolf rearrangement with Et3N in THF/H2O catalyzed by AgOBz and benzylation with benzyl bromide and DBU in acetonitrile. Conversion of (II) into azetidinone derivative (III) is achieved by Boc group removal by means of HCl in dioxane followed by cyclization by treatment with TMSCl, Et3N in Et2O and then t-BuMgCl. Protection of (III) using TIPSOTf and 2,5-lutidine in CH2Cl2 followed by removal of benzyl ether by hydrogenolysis over Pd(OH)2 in THF gives beta-lactam alcohol (IV), which is then oxidized by means of Dess-Martin periodinane in CH2Cl2 to yield aldehyde (V). Reaction of (V) with benzothiazole (VI) and n-BuLi in THF yields alcohol (VII), which is then deoxygenated by treatment with 1,1-(thiocarbonyl)diimidazole and DMAP in CH2Cl2 followed by reduction with Ph3SnH and AIBN in benzene to afford (VIII). Removal of the TIPS group from (VIII) by means of CsF in MeOH followed by condensation with chloride (IX) by means of KHMDS in THF finally furnishes the target product.

参考文献中间体

合成目标

【1】 Ogilvie, W.W.; Naud, J.; Hache, B.; Yoakim, C.; O'Meara, J.A.; Do, F.; Deziel, R.; Lagace, L.; Synthesis and antiviral activity of monobactams inhibiting the human cytomegalovirus protease. Bioorg Med Chem 1999, 7, 8, 1521.
【2】 Ogilvie, W.W.; O'Meara, J.; Deziel, R.; Yoakim, C. (Boehringer Ingelheim (Canada) Ltd.); Azetidinone derivs. for the treatment of HCMV infections. EP 1021405; WO 9918072 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIa)	43532	(4R)-4-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-(triisopropylsilyl)-2-azetidinone		C₂₀H₃₀N₂O₂SSi	详情	详情
(VIIb)	43533	(4R)-4-[(S)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-(triisopropylsilyl)-2-azetidinone		C₂₀H₃₀N₂O₂SSi	详情	详情
(I)	16886	(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine	23680-31-1	C₁₅H₂₁NO₅	详情	详情
(II)	43528	benzyl (3R)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]butanoate		C₂₃H₂₉NO₅	详情	详情
(III)	43529	(4R)-4-[(benzyloxy)methyl]-2-azetidinone		C₁₁H₁₃NO₂	详情	详情
(IV)	43530	(4R)-4-(hydroxymethyl)-1-(triisopropylsilyl)-2-azetidinone		C₁₃H₂₇NO₂Si	详情	详情
(V)	43531	(2R)-4-oxo-1-(triisopropylsilyl)-2-azetidinecarbaldehyde		C₁₃H₂₅NO₂Si	详情	详情
(VI)	36784	1,3-benzothiazole	95-16-9	C₇H₅NS	详情	详情
(VIII)	43534	(4R)-4-(1,3-benzothiazol-2-ylmethyl)-1-(triisopropylsilyl)-2-azetidinone		C₂₀H₃₀N₂OSSi	详情	详情
(IX)	28425	1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene		C₁₀H₉ClF₃NO	详情	详情

Extended Information