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【结 构 式】 
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【分子编号】30212 【品名】1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate 【CA登记号】33375-06-3 |
【 分 子 式 】C9H9NO 【 分 子 量 】147.1766 【元素组成】C 73.45% H 6.16% N 9.52% O 10.87% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)aniline (I) with (R)-1-phenylethyl isocyanate (II) at low temperature gives a mixture of the urea (III) and tetrahydroquinazolinone (IV). Without isolation the urea (III) is cyclized to the tetrahydroquinazolinone (IV) by heating at 60 C. The dehydration of (IV) by means of SOCl2 and TEA in toluene affords the quinazolinone (V), which, without isolation, is condensed with the cyclopropylacetylide (VI) in THF to provide the alkylated tetrahydroquinazolinone (VII). Finally, this compound is deprotected from the chiral auxiliary by means of TFA or formic acid.
| 【1】 Magnus, N.A.; et al.; A new asymmetric 1,4-addition method: Application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961. Tetrahedron Lett 2000, 41, 17, 3015. |
| 【2】 Confalone, P.N.; Magnus, N.A.; Storace, L. (DuPont Pharmaceuticals Co.); Process for the preparation of quinazolinones. WO 0029391 . |
| 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) | 50015 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1,1-ethanediol | C8H7ClF3NO2 | 详情 | 详情 | |
| (II) | 30212 | 1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate | 33375-06-3 | C9H9NO | 详情 | 详情 |
| (III) | 50016 | N-[4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)phenyl]-N'-[(1R)-1-phenylethyl]urea | C17H16ClF3N2O3 | 详情 | 详情 | |
| (IV) | 50017 | (4S)-6-chloro-4-hydroxy-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C17H14ClF3N2O2 | 详情 | 详情 | |
| (V) | 50018 | 6-chloro-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-2(3H)-quinazolinone | C17H12ClF3N2O | 详情 | 详情 | |
| (VI) | 50019 | bromo(2-cyclopropylethynyl)magnesium | C5H5BrMg | 详情 | 详情 | |
| (VII) | 50020 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C22H18ClF3N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The acylation of 2-pyridylmethanol (I) with thioacetic acid (II) by means of Ph3P and DEAD in THF gives the corresponding thioacetate (III), which is condensed with 4-acetoxyazetidin-2-one (IV) by means of NaOH in methanol yielding 4-(2-pyridylmethylsulfanyl)azetidin-2-one (V). Finally, this compound is condensed with 1(R)-phenylethyl isocyanate (VI) by means of Et3N and DMAP in dichloromethane.
| 【1】 Deziel, R.; Malenfant, E.; Inhibition of human cytomegalovirus protease N(o) with monocyclic beta-lactams. Bioorg Med Chem Lett 1998, 8, 11, 1437. |
| 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) | 30208 | 2-pyridinylmethanol；pyridin-2-ylmethanol；2-pyridylmethanol | 586-98-1 | C6H7NO | 详情 | 详情 |
| (II) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (III) | 30209 | S-(2-pyridinylmethyl) ethanethioate | C8H9NOS | 详情 | 详情 | |
| (IV) | 30210 | 4-oxo-2-azetidinyl acetate | C5H7NO3 | 详情 | 详情 | |
| (V) | 30211 | 4-[(2-pyridinylmethyl)sulfanyl]-2-azetidinone | C9H10N2OS | 详情 | 详情 | |
| (VI) | 30212 | 1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate | 33375-06-3 | C9H9NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)DPC-961 (I) can be obtained by several different related ways: 3) Condensation of 4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)aniline (XI) with (R)-1-phenylethyl isocyanate (XII) by means of HCl at low temperature gives a mixture of the urea (XIII) and tetrahydroquinazolinone (XIV). Without isolation, urea (XIII) is cyclized to the tetrahydroquinazolinone (XIV) by heating at 60 C. Dehydration of (XIV) by means of SOCl2 and Et3N in toluene affords the quinazolinone (XV), which, without isolation, is condensed with the Grignard reagent bromomagnesium cyclopropylacetylide (XVI) in THF to provide the alkylated tetrahydroquinazolinone (XVII). Finally, compound (XVII) is deprotected from the chiral auxiliary by means of TFA or formic acid. 4) Condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (II) with (R)-1-phenylethyl isocyanate (XII) by means of either HCl in THF or TMSCl/THF in toluene, followed by heating at 60-65 C, provides the tetrahydroquinazolinone (XIX). Dehydration of (XIX) with SOCl2 and Et3N or NMM in toluene affords quinazolinone (XV), which, without isolation, is condensed with the Grignard reagent chloromagnesium cyclopropylacetylide (XX) to give the tetrahydroquinazoline (XVII). Finally, this compound is treated with TFA or formic acid as before.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Leeson, P.A.; DPC-083. Drugs Fut 2002, 27, 4, 331. |
| 【2】 Magnus, N.A.; et al.; A new asymmetric 1,4-addition method: Application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961. Tetrahedron Lett 2000, 41, 17, 3015. |
| 【3】 Confalone, P.N.; Magnus, N.A.; Storace, L. (DuPont Pharmaceuticals Co.); Process for the preparation of quinazolinones. WO 0029391 . |
| 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) | 36613 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C14H10ClF3N2O | 详情 | 详情 | |
| (II) | 16572 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone | C8H5ClF3NO | 详情 | 详情 | |
| (X) | 50015 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1,1-ethanediol | C8H7ClF3NO2 | 详情 | 详情 | |
| (XI) | 30212 | 1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate | 33375-06-3 | C9H9NO | 详情 | 详情 |
| (XII) | 50016 | N-[4-chloro-2-(2,2,2-trifluoro-1,1-dihydroxyethyl)phenyl]-N'-[(1R)-1-phenylethyl]urea | C17H16ClF3N2O3 | 详情 | 详情 | |
| (XIII) | 50017 | (4S)-6-chloro-4-hydroxy-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C17H14ClF3N2O2 | 详情 | 详情 | |
| (XIV) | 50018 | 6-chloro-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-2(3H)-quinazolinone | C17H12ClF3N2O | 详情 | 详情 | |
| (XV) | 50019 | bromo(2-cyclopropylethynyl)magnesium | C5H5BrMg | 详情 | 详情 | |
| (XVI) | 50020 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-3-[(1R)-1-phenylethyl]-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C22H18ClF3N2O | 详情 | 详情 | |
| (XVII) | 52671 | N-[4-chloro-2-(2,2,2-trifluoroacetyl)phenyl]-N'-(1-phenylethyl)urea | C17H14ClF3N2O2 | 详情 | 详情 | |
| (XVIII) | 52670 | chloro(2-cyclopropylethynyl)magnesium | C5H5ClMg | 详情 | 详情 | |
| (XIX) | 52672 | 6-chloro-4-hydroxy-3-(1-phenylethyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone | C17H14ClF3N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Progesterone (I) was oxidized to the 6-dehydro derivative (II) using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Conjugate addition of 4-aminothiophenol (III) to dienone (II) furnished the aminophenyl sulfide (IV). The target urea was then obtained by coupling of the amino compound (IV) with (R)-alpha-methylbenzyl isocyanate (V).
| 【1】 Clarke, R.; Leonessa, F.; Ghiorghis, A.; Kulawiec, R.J.; Talebian, A.; Kim, J.-H.; Hammer, C.; C-7 analogues of progesterone as potent inhibitors of the P-glycoprotein efflux pump. J Med Chem 2002, 45, 2, 390. |
| 【2】 Clarke, R.; Talebian, A.H.; Ghiorghis, A.; Leonessa, F.; Hammer, C. (Georgetown University); Progesterone analogs to reverse multidrug resistance. WO 9700683 . |
| 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) | 55957 | (9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one; (S)-Pregn-4-en-3,20-dione; 3,20-pregnene-4; 4-Pregnene-3,20-dione; beta-progesterone; Corlutin; Corlutina; Corluvite; Corporin; Corpus luteum hormone; Flavolutan; Fologenon; Gestone; Gestormone; Glanducorpin; Homoflaveine; Hormoluton; Lipolutin; Lucorteum; Luteal hormone; Lutein; Luteinique; Luteodyn; Luteogan; Luteohormone; Luteol; Luteosan; Luteostab; Luteovis; Lutex; Lutidon; Lutocyclin; Lutocylin; Lutocylol; Lutoform; Lutogyl; Lutren; Lutromone; Piaponon; Pranone; Pregn-4-ene-3,20-dione; pregnendione; Pregnene-3,20-dione; Pregnenedione; Primolut; Progekan; Progesterol; Progesterone; Progesteronum; Progestone; Prolidon; Syntolutan | 57-83-0 | C21H30O2 | 详情 | 详情 |
| (II) | 55958 | (9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | 1162-56-7 | C21H28O2 | 详情 | 详情 |
| (III) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (IV) | 55959 | (7R,9S,10R,13S,14S,17S)-17-acetyl-7-[(4-aminophenyl)sulfanyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C27H35NO2S | 详情 | 详情 | |
| (V) | 30212 | 1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate | 33375-06-3 | C9H9NO | 详情 | 详情 |