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【结 构 式】 
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【分子编号】25975 【品名】1,1,1-trichloro-2-methyl-2-propanol 【CA登记号】57-15-8 |
【 分 子 式 】C4H7Cl3O 【 分 子 量 】177.45708 【元素组成】C 27.07% H 3.98% Cl 59.93% O 9.02% |
合成路线1
该中间体在本合成路线中的序号：(III)The N-protection of 4-(2-aminoethyl)phenol (I) with benzyl chloroformate gives the N-benzyloxycarbonyl derivative (II), which is condensed with 1-methyl-1-(trichloromethyl)ethanol (III) by means of NaOH in acetone yielding the phenoxyisobutyric acid (IV). The deprotection of the amino group of (IV) by hydrogenation over Pd/C affords the ethylamino derivative (V), which is reprotected with 9-fluorenylmethoxycarbonyl protecting group to provide carbamate (VI). The acid group of (VI) is then coupled to a Sasrin polystyrene resin giving the N-protected resin (VII), which is deprotected with piperidine affording resin (VIII) with a free amino group, which is condensed with heptanoic acid (A) by means of DIC and HOBT to give the amide (IX). The reduction of the carbonyl group amide (IX) with BH3/THF yields the heptylamine (X), which is condensed with 4-fluorophenyl isocyanate (XI) to afford the urea (XII). Finally, this compound is treated with trifluoroacetic acid to eliminate the polystyrene resin and isolate the target compound. Alternatively, the heptylamine (X) can also be obtained directly by reductocondensation of the free amino group of the resin (VIII) with heptanal (B) by means of NaBH3CN.
| 【1】 Brown, P.J.; et al.; Generation of secondary alkyl amines on solid support by borane reduction. Application to the parallel synthesis of PPAR ligands. Synthesis 1997, 7, 778. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 | |
| (B) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (A) | 35032 | heptanoic acid | 111-14-8 | C7H14O2 | 详情 | 详情 |
| (I) | 19988 | 4-(2-Aminoethyl)phenol; Tyramine | 51-67-2 | C8H11NO | 详情 | 详情 |
| (II) | 25974 | benzyl 4-hydroxyphenethylcarbamate | C16H17NO3 | 详情 | 详情 | |
| (III) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
| (IV) | 25976 | 2-[4-(2-[[(benzyloxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid | C20H23NO5 | 详情 | 详情 | |
| (V) | 25977 | 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionic acid | C12H17NO3 | 详情 | 详情 | |
| (VI) | 25978 | 2-[4-(2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid | C27H27NO5 | 详情 | 详情 | |
| (VII) | 25978 | 2-[4-(2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid | C27H27NO5 | 详情 | 详情 | |
| (VIII) | 25977 | 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionic acid | C12H17NO3 | 详情 | 详情 | |
| (IX) | 25979 | 2-[4-[2-(heptanoylamino)ethyl]phenoxy]-2-methylpropionic acid | C19H29NO4 | 详情 | 详情 | |
| (X) | 25980 | 2-[4-[2-(heptylamino)ethyl]phenoxy]-2-methylpropionic acid | C19H31NO3 | 详情 | 详情 | |
| (XI) | 17977 | 1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate | 1195-45-5 | C7H4FNO | 详情 | 详情 |
| (XII) | 25981 | 2-(4-[2-[[(4-fluoroanilino)carbonyl](heptyl)amino]ethyl]phenoxy)-2-methylpropionic acid | C26H35FN2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of 3-bromophenol (I) with 2,2,2-trichloro-1,1-dimethylethanol (II) by means of NaOH in acetone gives 2-(3-bromophenoxy)-2-methylpropionic acid (III), which is esterified with isobutylene and H2SO4, yielding the corresponding tert-butyl ester (IV). The condensation of (IV) with N-allylphthalimide (V) by means of Pd(OAc)2, tri(o-tolyl)phosphine and DIEA in acetonitrile, followed by hydrogenation with H2 over Pd/C, affords the adduct (VI). The reaction of (VI) with hydrazine in refluxing ethanol cleaves the phthalimido group to provide the amino derivative (VII), which is treated with 3,5-dinitrophenylsulfonyl chloride (VIII) and TEA in dichloromethane to give the sulfonamide (IX). The cleavage of the tert-butyl ester group of (IX) with TFA in dichloromethane yields the carboxylic acid (X), which is esterified with SASRIN resin (XI) by means of 1,3-dimethyl-2-fluoro p-toluenesulfonate (DMFPT) in dichloromethane to afford the resin-anchored polyester (XII). The N-alkylation of (XII) with 2,4-bis(trifluoromethyl)benzyl alcohol (XIII) by means of PPh3 and DIAD in THF provides the disubstituted sulfonamide (XIV). The cleavage of the sulfonamido group of (XIV) by means of mercaptoacetic acid and TEA in dichloromethane gives the resin-bound secondary amine (XV), which is acylated with 2-[4-(trifluoromethyl)phenyl]acetic acid (XVI) by means of HATU and DIEA to yield the acetamide precursor (XVII). Finally, the title product is cleaved from the resin (XVII) by treatment with TFA in dichloromethane.
| 【1】 Liu, K.G.; Lambert, M.H.; Leesnitzer, L.M.; et al.; Identification of a series of PPARgamma/delta dual agonists via solid-phase parallel synthesis. Bioorg Med Chem Lett 2001, 11, 22, 2959. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X),(XII) | 54445 | 2-[3-(3-{[(3,5-dinitrophenyl)sulfonyl]amino}propyl)phenoxy]-2-methylpropanoic acid | C19H21N3O9S | 详情 | 详情 | |
| (I) | 20704 | 3-bromophenol | 591-20-8 | C6H5BrO | 详情 | 详情 |
| (II) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
| (III) | 54439 | 2-(3-bromophenoxy)-2-methylpropanoic acid | C10H11BrO3 | 详情 | 详情 | |
| (IV) | 54440 | tert-butyl 2-(3-bromophenoxy)-2-methylpropanoate | C14H19BrO3 | 详情 | 详情 | |
| (V) | 46464 | 2-allyl-1H-isoindole-1,3(2H)-dione | C11H9NO2 | 详情 | 详情 | |
| (VI) | 54441 | tert-butyl 2-{3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenoxy}-2-methylpropanoate | C25H29NO5 | 详情 | 详情 | |
| (VII) | 54442 | tert-butyl 2-[3-(3-aminopropyl)phenoxy]-2-methylpropanoate | C17H27NO3 | 详情 | 详情 | |
| (VIII) | 54443 | 3,5-dinitrobenzenesulfonamide | C6H5N3O6S | 详情 | 详情 | |
| (IX) | 54444 | tert-butyl 2-[3-(3-{[(3,5-dinitrophenyl)sulfonyl]amino}propyl)phenoxy]-2-methylpropanoate | C23H29N3O9S | 详情 | 详情 | |
| (XIII) | 54446 | [2,4-bis(trifluoromethyl)phenyl]methanol | C9H6F6O | 详情 | 详情 | |
| (XIV) | 54447 | 2-[3-(3-{[2,4-bis(trifluoromethyl)benzyl][(3,5-dinitrophenyl)sulfonyl]amino}propyl)phenoxy]-2-methylpropanoic acid | C28H25F6N3O9S | 详情 | 详情 | |
| (XV) | 54448 | 2-[3-(3-{[2,4-bis(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoic acid | C22H23F6NO3 | 详情 | 详情 | |
| (XVI) | 54449 | 2-[4-(trifluoromethyl)phenyl]acetic acid | 32857-62-8 | C9H7F3O2 | 详情 | 详情 |
| (XVII) | 54450 | 2-{3-[3-([2,4-bis(trifluoromethyl)benzyl]{2-[4-(trifluoromethyl)phenyl]acetyl}amino)propyl]phenoxy}-2-methylpropanoic acid | C31H28F9NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)2-(4-Hydroxyphenyl)ethanol (I) was protected at the aliphatic hydroxyl group by the following sequence. Reaction of (I) with methoxymethyl chloride and NaH blocked the phenolic hydroxyl as the methoxymethyl ether (II), which was subsequently treated with benzyl bromide to produce the fully protected compound (III). Further hydrolysis of the methoxymethyl ether using trifluoroacetic acid gave rise to 4-(2-benzyloxyethyl)phenol (IV). Condensation of phenol (IV) with 1,1,1-trichloro-2-methyl-2-propanol (V) under basic conditions generated the 2-(aryloxy)isobutyric acid (VI). After esterification of (VI) with SOCl2 in EtOH to give (VII), its O-benzyl protecting group was removed by catalytic hydrogenation to produce (VIII). Alcohol (VIII) was then converted into alkyl bromide (IX) by using CBr4 and PPh3. Alkylation of (-)-4'-hydroxynorephedrine (X) with bromide (IX) in hot DMF afforded the secondary amine (XI). The ethyl ester group of (XI) was finally hydrolyzed with NaOH to the title carboxylic acid.
| 【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265. |
| 【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hiribayashi, A. (Kissei Pharmaceutical Co., Ltd.); 2-Methylpropionic acid derivs. and medicinal compsns. containing the same. EP 1072583; WO 9952856 . |
| 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) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
| (II) | 56061 | sodium 2-[4-(methoxymethoxy)phenyl]-1-ethanolate | C10H13NaO3 | 详情 | 详情 | |
| (III) | 56062 | benzyl 4-(methoxymethoxy)phenethyl ether; 1-[2-(benzyloxy)ethyl]-4-(methoxymethoxy)benzene | C17H20O3 | 详情 | 详情 | |
| (IV) | 56063 | 4-[2-(benzyloxy)ethyl]phenol | C15H16O2 | 详情 | 详情 | |
| (V) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
| (VI) | 56064 | 2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoic acid | C19H22O4 | 详情 | 详情 | |
| (VII) | 56065 | ethyl 2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoate | C21H26O4 | 详情 | 详情 | |
| (VIII) | 56066 | ethyl 2-[4-(2-hydroxyethyl)phenoxy]-2-methylpropanoate | C14H20O4 | 详情 | 详情 | |
| (IX) | 56067 | ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate | C14H19BrO3 | 详情 | 详情 | |
| (X) | 46836 | 4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol | C9H13NO2 | 详情 | 详情 | |
| (XI) | 56068 | ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropanoate | C23H31NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)An alternative route to the intermediate bromide (IX) has been reported. Condensation of phenol (XII) with 1,1,1-trichloro-2-methyl-2-propanol (V) led to 2-phenoxyisobutyric acid (XIII), which was further esterified by treatment with SOCl2 in EtOH to yield (XIV). Friedel-Crafts acylation of (XIV) with bromoacetyl bromide (XV) in the presence of AlCl3 provided the phenacyl bromide (XVI). The corresponding phenethyl bromide (IX) was then obtained by reduction of ketone (XVI) with triethylsilane in trifluoroacetic acid.
| 【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
| (IX) | 56067 | ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate | C14H19BrO3 | 详情 | 详情 | |
| (XII) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XIII) | 56069 | 2-methyl-2-phenoxypropanoic acid | C10H12O3 | 详情 | 详情 | |
| (XIV) | 56070 | ethyl 2-methyl-2-phenoxypropanoate | C12H16O3 | 详情 | 详情 | |
| (XV) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XVI) | 56071 | ethyl 2-[4-(2-bromoacetyl)phenoxy]-2-methylpropanoate | C14H17BrO4 | 详情 | 详情 |