|
【结 构 式】 
|
【分子编号】44796 【品名】4-phenoxybenzoyl chloride 【CA登记号】 |
【 分 子 式 】C13H9ClO2 【 分 子 量 】232.66596 【元素组成】C 67.11% H 3.9% Cl 15.24% O 13.75% |
合成路线1
该中间体在本合成路线中的序号：(II)Coupling of 4(S)-amino-4-carboxybutyric acid methyl ester (I) to acyl chloride (II) by means of Et3N in CH2Cl2 provides derivative (III), which is then converted into hydroxy derivative (IV) by means of N-hydroxysuccinimide (A) and DCC in THF followed by reduction with NaBH4 in H2O. Treatment of (IV) with ethoxymethylchloride (V) and DIEA in CH2Cl2 affords compound (VI), which is then methylated by means of lithium bis(trimethylsilyl)amide and methyl iodide in THF to give derivative (VII). Saponification of methyl ester (VII) by treatment with aqueous NaOH in THF affords carboxylic acid (VIII), which is then coupled to N-(1-methoxy-1,1-dimethyloxy)amine (IX) by means of HOBt and EDC in DMF and finally hydrolyzed with HCl in MeOH to furnish the target compound.
| 【1】 Sugiura, T.; Takahashi, K. (Ono Pharmaceutical Co., Ltd.); Aminobutanoic acid derivs.. EP 1024134; WO 9919296 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (I) | 44795 | (2S)-2-amino-5-methoxy-5-oxopentanoic acid | 1499-55-4 | C6H11NO4 | 详情 | 详情 |
| (II) | 44796 | 4-phenoxybenzoyl chloride | C13H9ClO2 | 详情 | 详情 | |
| (III) | 44797 | (2S)-5-methoxy-5-oxo-2-[(4-phenoxybenzoyl)amino]pentanoic acid | C19H19NO6 | 详情 | 详情 | |
| (IV) | 44798 | methyl (4S)-5-hydroxy-4-[(4-phenoxybenzoyl)amino]pentanoate | C19H21NO5 | 详情 | 详情 | |
| (V) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (VI) | 44799 | methyl (4S)-5-(ethoxymethoxy)-4-[(4-phenoxybenzoyl)amino]pentanoate | C22H27NO6 | 详情 | 详情 | |
| (VII) | 44800 | methyl (2S,4S)-5-(ethoxymethoxy)-2-methyl-4-[(4-phenoxybenzoyl)amino]pentanoate | C23H29NO6 | 详情 | 详情 | |
| (VIII) | 44801 | (2S,4S)-5-(ethoxymethoxy)-2-methyl-4-[(4-phenoxybenzoyl)amino]pentanoic acid | C22H27NO6 | 详情 | 详情 | |
| (IX) | 44802 | 2-(aminooxy)-2-methoxypropane; O-(1-methoxy-1-methylethyl)hydroxylamine | C4H11NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)4-Phenoxybenzoic acid (I) is chlorinated with SOCl2, and the resultant acid chloride (II) is then condensed with malononitrile to produce the hydroxybenzylidene malononitrile (III). Subsequent methylation of (III) with trimethylsilyl diazomethane yields the methyl ether (IV), which is cyclized to pyrazole (V) upon treatment with hydrazine hydrate in boiling EtOH. Reaction of the 3-amino-4-cyanopyrazole (V) with hot formamide then produces the key pyrazolopyrimidine intermediate (VI).
| 【1】 Hirst, G.C.; Rafferty, P.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D.; Friedman, M.M. (BASF AG); Pyrazolopyrimidines as therapeutic agents. EP 1212327; WO 0119829 . |
| 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) | 57044 | 4-Phenoxybenzoic acid; Diphenyl ether 4-carboxylic acid | 2215-77-2 | C13H10O3 | 详情 | 详情 |
| (II) | 44796 | 4-phenoxybenzoyl chloride | C13H9ClO2 | 详情 | 详情 | |
| (III) | 57045 | 2-[hydroxy(4-phenoxyphenyl)methylene]malononitrile | C16H10N2O2 | 详情 | 详情 | |
| (IV) | 57046 | 2-[methoxy(4-phenoxyphenyl)methylene]malononitrile | C17H12N2O2 | 详情 | 详情 | |
| (V) | 57047 | 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile | C16H12N4O | 详情 | 详情 | |
| (VI) | 57048 | 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C17H13N5O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Chlorination of 4-phenoxybenzoic acid (I) with refluxing SOCl2 gives the corresponding acid chloride (II), which is then condensed with malononitrile (III) in the presence of DIEA in toluene/THF, followed by treatment with H2So4 to yield the enol derivative (IV). Methylation of the hydroxy group of compound (IV) by means of Me3SiCHn2 and DIEA in ace tonitrile/MeoH provides the 2-methoxyethene derivative (V), which by cyclization with hydrazine in EtoH affords the pyrazole derivative (VI). Cyclization of compound (VI) with formamide at 180 °C gives 4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine (VII) (1), which is submitted to Mitsunobu coupling with N-Boc-3(S)-hydroxypiperidine (VIII) in THF using DIAD and either polymer-bound triphenylphosphine or PPh3 to provide the 1-[N-Boc-3(R)-piperidinyl]pyrazolopyrimidine derivative (IX). Deprotection of intermediate (IX) by treatment with HCl in dioxane or TFA in CH2Cl2 leads to the free piperidine derivative (X), which is finally acylated with acryloyl chloride (XI) by means of Et3n in CH2Cl2 .
| 【1】 Hirst, G.C., Wishart, n., Rafferty, P., Friedman, M.M., Arnold, L.D., Calderwood, D., Ritter, K. (Abbott GmbH & Co. KG). Pyrazolopyrimidines as therapeutic agents. EP 1212327, JP 2003509428, US 6660744, WO 2001019829. |
| 【2】 Pan, Z., Scheerens, H., Li, S.J. et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. ChemMedChem 2007, 2(1): 58-61. |
| 【3】 Honigberg, L., Verner, E., Pan, Z. (Pharmacyclics, Inc.). Inhibitors of Bruton’s tyrosine kinase. US 2008139582, US 7825118. |
| 【4】 Honigberg, L., Verner, E., Pan, Z. (Pharmacyclics, Inc.). Inhibitors of Bruton’s tyrosine kinase. KR 2013027536, US 2008076921, US 7732454. |
| 【5】 Honigberg, L., Verner, E., Pan, Z. (Pharmacyclics, Inc.). Inhibitors of Bruton’s tyrosine kinase. CA 266116, Cn 101805341, Cn 102746305, CN 102887900, EP 2081435, EP 2201840, EP 2443929, EP 2526771, EP 2526933, EP 2526934, EP 2529621, EP 21529622, EP 2532234, EP 2532235, JP 2010504324, JP 2010235628, US 2008108636, US 7514444, WO 2008039218. |
| 【6】 Pan, Z., Li, S.J., Schereens, H., Honigberg, L., Verner, E. (Pharmacyclics, Inc.). Bruton’s tyrosine kinase activity probe and method of using. US 2008214501, WO 2008054827. |
| 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) | 57044 | 4-Phenoxybenzoic acid; Diphenyl ether 4-carboxylic acid | 2215-77-2 | C13H10O3 | 详情 | 详情 |
| (II) | 44796 | 4-phenoxybenzoyl chloride | C13H9ClO2 | 详情 | 详情 | |
| (III) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (IV) | 57045 | 2-[hydroxy(4-phenoxyphenyl)methylene]malononitrile | C16H10N2O2 | 详情 | 详情 | |
| (V) | 57046 | 2-[methoxy(4-phenoxyphenyl)methylene]malononitrile | C17H12N2O2 | 详情 | 详情 | |
| (VI) | 57047 | 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile | C16H12N4O | 详情 | 详情 | |
| (VII) | 57048 | 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C17H13N5O | 详情 | 详情 | |
| (VIII) | 68045 | (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate | 143900-44-1 | C10H19NO3 | 详情 | 详情 |
| (IX) | 68047 | (R)-tert-butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate | C27H30N6O3 | 详情 | 详情 | |
| (X) | 68046 | (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | C22H22N6O | 详情 | 详情 | |
| (XI) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |