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【结 构 式】 
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【分子编号】44234 【品名】1-methyl-1H-pyrazole; N-Methylpyrazole 【CA登记号】930-36-9 |
【 分 子 式 】C4H6N2 【 分 子 量 】82.10512 【元素组成】C 58.52% H 7.37% N 34.12% |
合成路线1
该中间体在本合成路线中的序号：The key compound 5-(alpha-hydroxybenzyl)-1-methyl-1H-pyrazole [(±)-I] was obtained by two related ways: 1) by condensation of N-methylpyrazole with benzonitrile and butyl lithium in tetrahydrofuran and reduction of the obtained ketone with sodium borohydride in methanol or 2) by condensation of N-methylpyrazole with benzaldehyde and butyl lithium in THF/toluene. The alkylation of [(±)-I] with 2-(dimethylamino)ethyl chloride hydrochloride was carried out using phase transfer conditions and reaction with citric acid using propanone as solvent.
| 【1】 Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721. |
| 【2】 Colombo, A.; Pares, J.; Frigola, J. (Laboratorios del Dr. Esteve, SA); Aryl-heteroaryl-carbinol derivs. having an analgesic activity. EP 0289380; FR 2613720; JP 1988267761; US 5017596 . |
合成路线2
该中间体在本合成路线中的序号：(I)Lithiation of N-methylpyrazole (I) by means of n-butyllithium, followed by addition to 2-thiophenecarboxaldehyde (II), afforded carbinol (III). This compound was alternatively obtained by sodium borohydride reduction of diheteroaryl ketone (IV). Condensation of alcohol (III) with either 2-(dimethylamino)ethyl chloride (IV) in the presence of NaOH or 2-(dimethylamino)ethanol (VI) under catalysis of H2SO4 furnished ether (VII). This compound was finally converted to the title citrate salt by treatment with citric acid in EtOH.
| 【1】 Frigola-Constansa, J.; Andaluz-Mataro, B.; Merce-Vidal, R. (Laboratorios del Dr. Esteve, SA); Thienylazolylalcoxyethanamines, their preparation and their application as medicaments. WO 9952525 . |
| 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) | 44234 | 1-methyl-1H-pyrazole; N-Methylpyrazole | 930-36-9 | C4H6N2 | 详情 | 详情 |
| (II) | 30732 | 2-thiophenecarbaldehyde; Thiophene-2-carboxaldehyde | 98-03-3 | C5H4OS | 详情 | 详情 |
| (III) | 44235 | (1-methyl-1H-pyrazol-5-yl)(2-thienyl)methanol | C9H10N2OS | 详情 | 详情 | |
| (IV) | 44236 | (1-methyl-1H-pyrazol-5-yl)(2-thienyl)methanone | C9H8N2OS | 详情 | 详情 | |
| (V) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (VI) | 44237 | 2-(dimethylamino)-1-ethanol | 108-01-0 | C4H11NO | 详情 | 详情 |
| (VII) | 44238 | N,N-dimethyl-2-[(1-methyl-1H-pyrazol-5-yl)(2-thienyl)methoxy]-1-ethanamine; N,N-dimethyl-N-[2-[(1-methyl-1H-pyrazol-5-yl)(2-thienyl)methoxy]ethyl]amine | C13H19N3OS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)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 |