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【结 构 式】 
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【分子编号】67808 【品名】Isopropyl pinacolyl borate;Isopropoxyboronic acid pinacol ester;2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 【CA登记号】61676-62-8 |
【 分 子 式 】C9H19BO3 【 分 子 量 】186.059 【元素组成】C 58.10% H 10.29% B 5.81% O 25.80% |
合成路线1
该中间体在本合成路线中的序号：(V)Esterification of 5-chlorothiophene-2-carboxylic acid (I) with MeOH in the presence of H2SO4 at 53 °C gives the corresponding methyl ester (II), which is either brominated using Br2 and AlCl3 in CHCl3 or iodinated by means of BTMA-ICl2 and ZnCl2 in AcOH at 70 °C, yielding the corresponding 4-bromo- or 4-iodo-thiophenecarboxylates (IIIa or IIIb). Metalation of 1-methylpyrazole (IV) with BuLi in THF, followed by condensation with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (V) affords the pyrazolylboronate (VI), which is then condensed with either thienyl bromide (IIIa) or iodide (IIIb) by means of Pd(t-Bu3P)2 and K2CO3 in 1,4-dioxane/water at 70 °C to produce methyl 5-chloro-4-(1-methylpyrazol-5-yl)-2-thiophenecarboxylate (VII). Treatment of compound (VII) with NCS in THF at 70 °C gives the chloropyrazole derivative (VIII), which by ester hydrolysis with NaOH in H2O/MeOH/THF provides the corresponding carboxylic acid (IX). Condensation of acid (IX) with amine (X) by means of PyBroP and DIEA in CH2Cl2 gives amide (XI), which is finally deprotected with NH2NH2 in THF/MeOH (1). Scheme 1.Amine intermediate (X) is prepared by reduction of N-Boc-(3-fluorophenyl) alanine (XII) with BH3·THF in THF to afford the primary alcohol (XIII), which is then subjected to Mitsunobu coupling with phthalimide (XIV) using PPh3 and DIAD in THF to provide compound (XV). Finally, compound (XV) is deprotected by cleavage of the N-Boc group with HCl in MeOH .
| 【1】 Seefeld, M.A., Rouse, M.B., Heerding, D.A., Peace, S., Yamashita, D.S., McNulty, K.C. (GlaxoSmithKline, Inc.). Inhibitors of Akt activity. EP 2117523, JP 2010518110, JP 2011126896, KR 2012130298, US 2009209607, US 2010267759, US 8273782, US 8410158, US 2013231378, WO 2008098104. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 67806 | methyl 4-bromo-5-chlorothiophene-2-carboxylate | C6H4BrClO2S | 详情 | 详情 | |
| (IIIb) | 67807 | methyl 5-chloro-4-iodothiophene-2-carboxylate | C6H4ClIO2S | 详情 | 详情 | |
| (I) | 67804 | 5-chlorothiophene-2-carboxylic acid | 24065-33-6 | C5H3ClO2S | 详情 | 详情 |
| (II) | 67805 | methyl 5-chlorothiophene-2-carboxylate | C6H5ClO2S | 详情 | 详情 | |
| (IV) | 44234 | 1-methyl-1H-pyrazole; N-Methylpyrazole | 930-36-9 | C4H6N2 | 详情 | 详情 |
| (V) | 67808 | Isopropyl pinacolyl borate;Isopropoxyboronic acid pinacol ester;2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane | 61676-62-8 | C9H19BO3 | 详情 | 详情 |
| (VI) | 67809 | 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole | 847818-74-0 | C10H17BN2O2 | 详情 | 详情 |
| (VII) | 67810 | methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxylate | C10H9ClN2O2S | 详情 | 详情 | |
| (VIII) | 67811 | methyl 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxylate | C10H8Cl2N2O2S | 详情 | 详情 | |
| (IX) | 67812 | 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxylic acid | C9H6Cl2N2O2S | 详情 | 详情 | |
| (X) | 67813 | (S)-2-(2-amino-3-(3-fluorophenyl)propyl)isoindoline-1,3-dione | C17H15FN2O2 | 详情 | 详情 | |
| (XI) | 67814 | 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((S)-1-(1,3-dioxoisoindolin-2-yl)-3-(3-fluorophenyl)propan-2-yl)thiophene-2-carboxamide | C26H19Cl2FN4O3S | 详情 | 详情 | |
| (XII) | 67815 | (S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluorophenyl)propanoic acid | C14H18FNO4 | 详情 | 详情 | |
| (XIII) | 67816 | (S)-tert-butyl (1-(3-fluorophenyl)-3-hydroxypropan-2-yl)carbamate | 114873-01-7 | C14H20FNO3 | 详情 | 详情 |
| (XIV) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (XV) | 67817 | (S)-tert-butyl (1-(1,3-dioxoisoindolin-2-yl)-3-(3-fluorophenyl)propan-2-yl)carbamate | C22H23FN2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Intermediate (III) is prepared by protection of either 4-iodopyrazole (XIIIa) or 4-bromopyrazole (XIIIb) with ethyl vinyl ether (XIV) by means of HCl in toluene or CH2Cl2 to give the corresponding (1-ethoxyethyl)pyrazoles (XVa) and (XVb). Finally, pyrazole (XVa) is submitted to metal-halogen exchange by means of i-PrMgCl in THF, followed by condensation with isopropyl pinacol borate (XVI) (obtained by reaction of pinacol [XVII] with triisopropyl borate at reflux), or pyrazole (XVb) is condensed with methyl pinacol borate (XVIII) by means of i-PrMgCl·LiCl in THF .
| 【1】 Lin, Q., Meloni, D., Pan, Y. et al. Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction. Org Lett 2009, 11(9): 1999-2002. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIIa) | 69178 | 4-iodopyrazole;4-Iodo-1H-pyrazole | 3469-69-0 | C3H3IN2 | 详情 | 详情 |
| (XIIIb) | 69179 | C3H3BrN2 | 详情 | 详情 | ||
| (XVa) | 69180 | 1-(1-ethoxyethyl)-4-iodo-1H-pyrazole | C7H11IN2O | 详情 | 详情 | |
| (XVb) | 69181 | 4-bromo-1-(1-ethoxyethyl)-1H-pyrazole | C7H11BrN2O | 详情 | 详情 | |
| (III) | 68071 | 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole | C13H23BN2O3 | 详情 | 详情 | |
| (XIV) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (XVI) | 67808 | Isopropyl pinacolyl borate;Isopropoxyboronic acid pinacol ester;2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane | 61676-62-8 | C9H19BO3 | 详情 | 详情 |
| (XVII) | 68108 | 2,3-Dimethyl-2,3-butanediol;2,3-Dimethylbutane-2,3-diol;Tetramethylethylene glycol;pinacol | 76-09-5 | C6H14O2 | 详情 | 详情 |
| (XVIII) | 69182 | Methoxyboronic acid pinacol ester;2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane | 1195-66-0 | C7H15BO3 | 详情 | 详情 |