|
【结 构 式】 
|
【分子编号】15822 【品名】Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate 【CA登记号】14199-15-6 |
【 分 子 式 】C9H10O3 【 分 子 量 】166.1766 【元素组成】C 65.05% H 6.07% O 28.88% |
合成路线1
该中间体在本合成路线中的序号：(I)The racemic mixture containing the (R)-enantiomer BAY X 1005 (IV) can be prepared according to the following scheme: 4-Hydroxyphenylacetic acid methyl ester (I) is coupled with 2-chloromethylquinoline and potassium carbonate in DMF. The resulting product (II) is alkylated with cyclopentylbromide and sodium hydride in DMF to give product (III). Final saponification is undertaken with sodium hydroxide in methanol leading to the racemic carboxylic acid (IV).
| 【1】 Muller-Peddinghaus, R.; Raddatz, S.; BAY X 1005. Drugs Fut 1995, 20, 10, 996. |
| 【2】 Mohrs, K.; Raddatz, S.; Perzborn, E.; Fruchtmann, R.; Kohlsdorfer, C.; Müller-Peddinghaus, R.; Theisen, P. (Bayer AG); Substd. 4-(quinoline-2-yl-methoxy)phenyl-acetic acid derivs. AU 8935270; DE 3900261; EP 0344519; JP 1990019359; JP 1998053577; US 4970215 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10972 | 1-Bromocyclopentane; Cyclopentyl bromide | 137-43-9 | C5H9Br | 详情 | 详情 | |
| 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 | |
| (I) | 15822 | Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate | 14199-15-6 | C9H10O3 | 详情 | 详情 |
| (II) | 15823 | methyl 2-[4-(2-quinolinylmethoxy)phenyl]acetate | C19H17NO3 | 详情 | 详情 | |
| (III) | 15824 | methyl 2-cyclopentyl-2-[4-(2-quinolinylmethoxy)phenyl]acetate | C24H25NO3 | 详情 | 详情 | |
| (IV) | 15825 | 2-cyclopentyl-2-[4-(2-quinolinylmethoxy)phenyl]acetic acid | C23H23NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The acetylation of 5-bromopyridine-2-amine (I) with acetic anhydride in AcOH gives the expected amide (II), which is alkylated with ethylene by means of palladium acetate, tri p-tolylphosphine and triethylamine in hot acetonitrile to yield N-(5-vinylpyridin-2-yl)acetamide (III). The regioselective dihydroxylation of the vinyl group of (III) with AD-Mix-B in tert-butanol affords N-[5-(1(R),2-dihydroxyethyl)pyridin-2-yl]acetamide (IV), which is monotosylated with Ts-Cl in cool pyridine to give the tosylate (V). The reaction of (V) with potassium tert.-butoxide in THF yields the epoxide (VI), which is condensed with 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide (VII) in hot toluene/DMSO to provide the expected addition product (VIII). Finally, this compound is treated with 6N HCl on a steam bath. The intermediate 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide (VII) has been obtained as follows: The reaction of benzyl chloroformate (IX) with ethanolamine (X) by means of NaHCO3 in water gives the carbamate (XI), which is condensed with 2-(4-hydroxyphenyl)-N-methylacetamide (XII) (obtained by reaction of the corresponding methyl ester (XIII) with methylamine), by means of PPh3 and diisopropyl azodicarboxylate (DIAD) in THF yielding the intermediate (XIV). Finally, this compound is submitted to elimination of the carbamate protecting group by hydrogenation with H2 over Pd/C in methanol to provide the target intermediate (VII).
| 【1】 Dow, R.L. (Pfizer Inc.); beta-Adrenergic agonists to reduce a wasting condition. EP 0887079 . |
| 【2】 Devries, K.M.; Dow, R.L.; Wright, S.W. (Pfizer Inc.); Process for substd. pyridines. EP 0938476; WO 9821184 . |
| 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) | 12123 | 5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine | 1072-97-5 | C5H5BrN2 | 详情 | 详情 |
| (II) | 32490 | N-(5-bromo-2-pyridinyl)acetamide | C7H7BrN2O | 详情 | 详情 | |
| (III) | 32491 | N-(5-vinyl-2-pyridinyl)acetamide | C9H10N2O | 详情 | 详情 | |
| (IV) | 32492 | N-[5-[(1R)-1,2-dihydroxyethyl]-2-pyridinyl]acetamide | C9H12N2O3 | 详情 | 详情 | |
| (V) | 32493 | (2R)-2-[6-(acetamido)-3-pyridinyl]-2-hydroxyethyl 4-methylbenzenesulfonate | C16H18N2O5S | 详情 | 详情 | |
| (VI) | 32494 | N-[5-[(2R)oxiranyl]-2-pyridinyl]acetamide | C9H10N2O2 | 详情 | 详情 | |
| (VII) | 32495 | 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide | C11H16N2O2 | 详情 | 详情 | |
| (VIII) | 32496 | 2-[4-[2-([(2R)-2-[6-(acetamido)-3-pyridinyl]-2-hydroxyethyl]amino)ethoxy]phenyl]-N-methylacetamide | C20H26N4O4 | 详情 | 详情 | |
| (IX) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (X) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XI) | 32497 | benzyl 2-hydroxyethylcarbamate | 77987-49-6 | C10H13NO3 | 详情 | 详情 |
| (XII) | 32498 | 2-(4-hydroxyphenyl)-N-methylacetamide | C9H11NO2 | 详情 | 详情 | |
| (XIII) | 15822 | Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate | 14199-15-6 | C9H10O3 | 详情 | 详情 |
| (XIV) | 32499 | benzyl 2-[4-[2-(methylamino)-2-oxoethyl]phenoxy]ethylcarbamate | C19H22N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)The condensation of 2-(4-hydroxyphenyl)acetic acid methyl ester (XIII) with 2-(tert-butoxycarbonylamino)ethanol (XV) by means of diethyl azodicarboxylate (DEAD) in THF gives 2-[4-[2-(tert-butoxy carbonyl- amino)ethoxy]phenyl]acetic acid methyl ester (XVI), which is deprotected with TFA in dichloromethane yielding the 2-aminoethoxy derivative (XVII). The addition of (XVII) to the oxiranyl derivative (XVIII) in refluxing methanol affords the intermediate (XIX), which is reduced with SnCl2 in refluxing methanol to give the 6-aminopyridine derivative (XX). Finally, this compound is hydrolyzed to the target compound with KOH in methanol/water. The oxirane intermediate (XVIII) has been obtained by stereocontrolled reductive cyclization of 6-(2-bromoacetyl)tetrazolo[1,5-a]pyridine (XXI) with commercial (R)-Alpine Borane in THF.
| 【1】 Fisher, M.H.; Wyvratt, M.J. (Merck & Co., Inc.); Novel beta-adrenergic agonists. AU 9047392; EP 0377488; JP 1990231486; US 5030640 . |
| 【2】 Dow, R.L. (Pfizer Inc.); beta-Adrenergic agonists. EP 0824519; JP 1999504649; US 5977124; WO 9635671 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 15822 | Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate | 14199-15-6 | C9H10O3 | 详情 | 详情 |
| (XV) | 32500 | tert-butyl 2-hydroxyethylcarbamate | 26690-80-2 | C7H15NO3 | 详情 | 详情 |
| (XVI) | 32501 | methyl 2-(4-[2-[(tert-butoxycarbonyl)amino]ethoxy]phenyl)acetate | C16H23NO5 | 详情 | 详情 | |
| (XVII) | 32502 | methyl 2-[4-(2-aminoethoxy)phenyl]acetate | C11H15NO3 | 详情 | 详情 | |
| (XVIII) | 32504 | 6-[(2R)oxiranyl][1,2,3,4]tetraazolo[1,5-a]pyridine | C7H6N4O | 详情 | 详情 | |
| (XIX) | 32503 | methyl 2-[4-(2-[[(2R)-2-hydroxy-2-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-ylethyl]amino]ethoxy)phenyl]acetate | C18H21N5O4 | 详情 | 详情 | |
| (XX) | 32505 | methyl 2-[4-(2-[[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino]ethoxy)phenyl]acetate | C18H23N3O4 | 详情 | 详情 | |
| (XXI) | 32506 | 2-bromo-1-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-yl-1-ethanone | C7H5BrN4O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Formylation of methyl 4-hydroxyphenylacetate (I) by reaction with MgCl2 and formaldehyde in acetonitrile yields aldehyde (II), which is then brominated by means of NBS in DMF to provide bromo derivative (III). Treatment of (III) with methoxyethoxymethyl chloride and DIEA furnishes O-protected derivative (IV), which is then subjected to Suzuki reaction with boronic acid (V) catalyzed by Pd(PPh3)4 in refluxing toluene in the presence of Na2CO3 to afford biphenyl (VI). Treatment of (VI) with dimethyl-1-diazo-2-oxopropylphosphonate (VII) in MeOH in the presence of K2CO3 furnishes alkyne (VIII), which is then coupled with the iodo-benzonitrile (IX) by means of catalytic Pd(PPh3)2Cl2, CuI and Et3N in acetonitrile to provide indole (X). Saponification of the methyl ester group of (X) with NaOH in THF, followed by hydrolysis with HCl in EtOH, gives carboxylic acid (XI), which is finally converted into the desired product by transformation of the nitrile moiety into an amidine via standard Pinner/aminolysis conditions with NH3 in EtOH followed by treatment with refluxing HCl.
| 【1】 Young, W.B.; Kolesnikov, A.; Rai, R.; et al.; Optimization of a screening lead for factor VIIa/TF. Bioorg Med Chem Lett 2001, 11, 17, 2253. |
| 【2】 Young, W.B.; Kakimura, H.; Nakaike, S.; Taniguchi, K.; Kobayashi, Y.; Ishii, T.; Amada, H.; Miyata, N.; Kametani, S.; Optimization of a screening lead for factor VIIIA/TF. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 48. |
| 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) | 15822 | Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate | 14199-15-6 | C9H10O3 | 详情 | 详情 |
| (II) | 48883 | methyl 2-(3-formyl-4-hydroxyphenyl)acetate | C10H10O4 | 详情 | 详情 | |
| (III) | 48884 | methyl 2-(3-bromo-5-formyl-4-hydroxyphenyl)acetate | C10H9BrO4 | 详情 | 详情 | |
| (IV) | 48885 | methyl 2-[3-bromo-5-formyl-4-[(2-methoxyethoxy)methoxy]phenyl]acetate | C14H17BrO6 | 详情 | 详情 | |
| (V) | 40934 | 3-nitrophenylboronic acid | 13331-27-6 | C6H6BNO4 | 详情 | 详情 |
| (VI) | 48886 | methyl 2-[5-formyl-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate | C20H21NO8 | 详情 | 详情 | |
| (VII) | 32432 | 1-Diazo-2-oxopropylphosphonic acid dimethyl ester | C5H9N2O4P | 详情 | 详情 | |
| (VIII) | 48887 | methyl 2-[5-ethynyl-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate | C21H21NO7 | 详情 | 详情 | |
| (IX) | 48888 | N-(4-cyano-2-iodophenyl)methanesulfonamide | C8H7IN2O2S | 详情 | 详情 | |
| (X) | 48889 | methyl 2-[5-[5-cyano-1-(methylsulfonyl)-1H-indol-2-yl]-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate | C29H27N3O9S | 详情 | 详情 | |
| (XI) | 48890 | 2-[5-(5-cyano-1H-indol-2-yl)-6-hydroxy-3'-nitro[1,1'-biphenyl]-3-yl]acetic acid | C23H15N3O5 | 详情 | 详情 |