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【结 构 式】 
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【分子编号】38962 【品名】2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine 【CA登记号】3963-62-0 |
【 分 子 式 】C14H15N 【 分 子 量 】197.27984 【元素组成】C 85.24% H 7.66% N 7.1% |
合成路线1
该中间体在本合成路线中的序号：(V)Guanosine (I) was protected as the triacetate ester (II) and then chlorinated with POCl3 in the presence of dimethylaniline and tetraethylammonium chloride to give the 6-chloro derivative (III). Diazotization of (III) with tert-butyl nitrite, followed by a modified Sandmeyer reaction provided dichloro purine (IV). Substitution of the 6-chloro of (IV) by 2,2-diphenylethylamine (V) in the presence of diisopropylethylamine in refluxing isopropanol furnished the chloroadenosine derivative (VI), and subsequent removal of the acetate protecting groups of (VI) by hydrolysis with Na2CO3 in aqueous MeOH yielded the adenosine derivative (VII).
| 【1】 Gregson, M.; Ayres, B.E.; Ewan, G.B.; Ellis, F.; Knight, J. (Glaxo Wellcome plc); 2,6-Diaminopurine derivs.. EP 0680488; JP 1996505864; US 5925624; WO 9417090 . |
| 【2】 Keeling, S.E.; et al.; The discovery and synthesis of highly potent, A2A receptor agonists. Bioorg Med Chem Lett 2000, 10, 4, 403. |
| 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) | 38958 | Guanosine; 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one | 118-00-3 | C10H13N5O5 | 详情 | 详情 |
| (II) | 38959 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H19N5O8 | 详情 | 详情 | |
| (III) | 22299 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H18ClN5O7 | 详情 | 详情 | |
| (IV) | 25228 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H16Cl2N4O7 | 详情 | 详情 | |
| (V) | 38962 | 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine | 3963-62-0 | C14H15N | 详情 | 详情 |
| (VI) | 38960 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-3-furanyl acetate | C30H30ClN5O7 | 详情 | 详情 | |
| (VII) | 38961 | (2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C24H24ClN5O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Alternatively, condensation of 2,6-dichloropurine (VIII) with protected ribose (IX) at 140 C gave the ribofuranosyl purine (X). Subsequent displacement of the 6-chloro of (V) by amine (V), followed by hydrolysis of the benzoate esters afforded the intermediate (VII).
| 【1】 Gregson, M.; Ayres, B.E.; Ewan, G.B.; Ellis, F.; Knight, J. (Glaxo Wellcome plc); 2,6-Diaminopurine derivs.. EP 0680488; JP 1996505864; US 5925624; WO 9417090 . |
| 【2】 Keeling, S.E.; et al.; The discovery and synthesis of highly potent, A2A receptor agonists. Bioorg Med Chem Lett 2000, 10, 4, 403. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (IX) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (X) | 32565 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate | C31H22Cl2N4O7 | 详情 | 详情 | |
| (XI) | 38962 | 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine | 3963-62-0 | C14H15N | 详情 | 详情 |
| (XII) | 38963 | ((2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl benzoate | C45H36ClN5O7 | 详情 | 详情 | |
| (XIII) | 38961 | (2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C24H24ClN5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)2,2-Diphenylethylamine (I) is converted into the corresponding formamide (II) upon refluxing in ethyl formate. Subsequent dehydration of formamide (II) with phosphorus oxychloride in the presence of diisopropylamine furnishes isocyanide (III)
| 【1】 Hirth, B.H.; Sneddon, S.F.; Kane, J.L.; Vinick, F.; Qiao, S.; Nahill, S.R. (Genzyme Corp.); Modulators of TNF-alpha signaling. WO 0187849 . |
合成路线4
该中间体在本合成路线中的序号：(VI)The title compound was prepared by solid-phase synthesis on a Sasrin resin. The silylated m-hydroxyphenylacetic acid (I) was attached to the resin using DCC and DMAP to yield the acid-bound resin (II). The silyl group of (II) was then removed by treatment of resin (II) with tetrabutylammonium fluoride in THF. The resultant phenol (III) was coupled to 3-bromo-1-propanol (IV) under Mitsunobu conditions to afford the bromide functionalized resin (V). Displacement of the bromide ion of (V) with 2,2-diphenylethylamine (VI) furnished the secondary amine (VII), which was subjected to reductive alkylation with aldehyde (VIII) in the presence of NaBH(OAc)3 to produce the resin-bound product (IX). Cleavage from the solid support employing trifluoroacetic acid in CH2Cl2 provided the target carboxylic acid.
| 【1】 Collins, J.L.; et al.; Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 2002, 45, 10, 1963. |
| 【2】 Willson, T.M.; Collins, J.L.; Maloney, P.R.; Fivush, A.M.; Stewart, E.L. (GlaxoSmithKline plc); Chemical cpds.. WO 0224632 . |
| 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),(II) | 58560 | 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetic acid | C14H22O3Si | 详情 | 详情 | |
| (III) | 58561 | 2-(3-hydroxyphenyl)acetic acid | C8H8O3 | 详情 | 详情 | |
| (IV) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (V) | 58562 | 2-[3-(3-bromopropoxy)phenyl]acetic acid | C11H13BrO3 | 详情 | 详情 | |
| (VI) | 38962 | 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine | 3963-62-0 | C14H15N | 详情 | 详情 |
| (VII) | 58563 | 2-(3-{3-[(2,2-diphenylethyl)amino]propoxy}phenyl)acetic acid | C25H27NO3 | 详情 | 详情 | |
| (VIII) | 58564 | 2-chloro-3-trifluoromethyl benzaldehyde | 93118-03-7 | C8H4ClF3O | 详情 | 详情 |
| (IX) | 58565 | 2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetic acid | C33H31ClF3NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)In a solution-phase synthesis, 2,2-diphenylethylamine (VI) was reductively condensed with 2-chloro-3-(trifluoromethyl)benzaldehyde (VIII) using a polymer-supported borohydride resin to give the secondary amine (X). Mitsunobu coupling of methyl 3-hydroxyphenylacetate (XI) with 3-bromo-1-propanol (IV) afforded the bromopropyl ether (XII). Condensation of bromide (XII) with amine (X) in refluxing acetonitrile furnished amino ester (XIII). This was finally hydrolyzed with LiOH to the title carboxylic acid.
| 【1】 Willson, T.M.; Collins, J.L.; Maloney, P.R.; Fivush, A.M.; Stewart, E.L. (GlaxoSmithKline plc); Chemical cpds.. WO 0224632 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (VI) | 38962 | 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine | 3963-62-0 | C14H15N | 详情 | 详情 |
| (VIII) | 58564 | 2-chloro-3-trifluoromethyl benzaldehyde | 93118-03-7 | C8H4ClF3O | 详情 | 详情 |
| (X) | 58566 | N-[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenyl-1-ethanamine; N-[2-chloro-3-(trifluoromethyl)benzyl]-N-(2,2-diphenylethyl)amine | C22H19ClF3N | 详情 | 详情 | |
| (XI) | 58567 | methyl 2-(3-hydroxyphenyl)acetate | C9H10O3 | 详情 | 详情 | |
| (XII) | 58568 | methyl 2-[3-(3-bromopropoxy)phenyl]acetate | C12H15BrO3 | 详情 | 详情 | |
| (XIII) | 58569 | methyl 2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate | C34H33ClF3NO3 | 详情 | 详情 |