|
【结 构 式】 
|
【分子编号】67622 【品名】2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid hydrobromide 【CA登记号】 |
【 分 子 式 】C10H7BrN2O4.HBr 【 分 子 量 】379.993 【元素组成】C 31.61% H 2.12% Br 42.06% N 7.37% O 16.84% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)Condensation of compound (XXIX) or its free base with 1-benzoylpiperazine hydrochloride (IX) in the presence of CDI in DMF at 10 °C yields the corresponding carboxamide (XXX), which by Ullmann-Goldberg-Buchwald reaction with 3-methyl-1,2,4-triazole (III) using CuI, t-DAMCH and KOH in acetonitrile/H2O followed by addition of LiBr affords the lithium salt of azaindole (X), isolated as KBr co-crystal (XXXI). Finally, selective N-alkylation of compound (XXXI) with di-tert-butyl chloromethyl phosphate (XI) in the presence of K3PO4 and Et4NI or K2CO3 in acetonitrile/CH2Cl2 results in the phosphate ester (XIV) , which is finally hydrolyzed using AcOH in water .
| 【1】 Chen, K., Risatti, C., Bultman, M. et al. Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS-663068. J Org Chem 2014, 79(18): 8757-67. |
| 【2】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038709. |
| 【3】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038710. |
| 【4】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038711. |
| 【5】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038712. |
| 【6】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038716. |
| 【7】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038717. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 42239 | di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate；PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER | 229625-50-7 | C9H20ClO4P | 详情 | 详情 |
| (III) | 67601 | 3-methyl-1,2,4-triazole；3-Methyltriazole；3-Methyl-1H-1,2,4-triazole；3-Methyl-4H-1,2,4-triazole | 7170-01-6 | C3H5N3 | 详情 | 详情 |
| (IX) | 67606 | 1-benzoylpiperazine;4-Benzoylpiperazine;N-Benzoylpiperazine;(Phenyl)(piperazin-1-yl)methanone | 13754-38-6 | C11H14N2O | 详情 | 详情 |
| (XIV) | 67609 | (3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl di-tert-butyl phosphate | C33H42N7O8P | 详情 | 详情 | |
| (XXIX) | 67622 | 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid hydrobromide | C10H7BrN2O4.HBr | 详情 | 详情 | |
| (XXX) | 67623 | 1-(4-benzoylpiperazin-1-yl)-2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione | C21H19BrN4O4 | 详情 | 详情 | |
| (XXXI) | 67624 | lithium potassium 3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-ide bromide | C24H22LiN7O4.KBr | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)Friedel-Crafts acylation of 1-(phenylsulfonyl)pyrrole (XV) with chloroacetyl chloride (XVI) by means of AlCl3 in CH2Cl2 gives 2-chloro-1-[1-(phenylsulfonyl)pyrrol-3-yl]ethanone (XVII), which by condensation with sodium N-tosyl formamide (XVIII) (obtained by treatment of tosylamide (XIX) with NaOMe in MeOH to afford sodium tosylamide (XX), which is then formylated with HCOOEt in MeOH) using Bu4NBr in THF at 60 °C affords the corresponding keto amide (XXI). Decarbonylation of intermediate (XXI) by means of H2SO4 in MeOH at 60 °C followed by protection of the keto group with (CH2OH)2 using HC(OMe)3 produces acetal (XXII). Pictet-Spengler cyclization of protected amine (XXII) with (HCHO)n in the presence of TFA in CH2Cl2 affords the 1,5,6,7-tetrahydro-4H-pyrrolo[2,3-c]pyridin-4-one derivative (XXIII) , which by O-methylation with HC(OMe)3 using MsOH and CMNOOH in MeOH yields the enol ether (XXIV). Redox elimination of the tosyl group in compound (XXIV) by means of Na2S2O3 and Et3N gives the pyrrolo[2,3-c]pyridine derivative (XXV) , which can also be prepared by treatment of N-protected amine (XXIII) with HC(OMe)3 in the presence of MsOH or Tf2O and CMNOOH or AIBN . Oxidation of intermediate (XXV) with H2O2 using MeReO3 or phthalic anhydride in CH2Cl2 results in the pyridine-N-oxide (XXVI). Bromination of compound (XXVI) with PyBroP and K3PO4 in trifluorotoluene, followed by treatment with NaOH in i-PrOH at 80 °C yields the bromopyridine (XXVII), which by Friedel-Crafts C-3-acylation with methyl oxalyl chloride (VI) using AlCl3 in CH2Cl2/MeNO2 at 0 °C produces the keto ester (XXVIII). Hydrolysis of the methyl ester (XXVIII) with aqueous NaOH and subsequent treatment with HBr affords (7-bromo-4-methoxypyrrolo[2,3-c]pyridin-3-yl)(oxo)acetic acid hydrobromide salt (XXIX) .
| 【1】 Ueda, Y., Connolly, T.P., Kadow, J.F. et al. (Bristol-Myers Squibb Co.). Prodrugs of piperazine and substituted piperidine antiviral agents. CN 101941990; US 7745625; EP 1725569; JP 2007529519; US 2005209246; WO 2005090367. |
| 【3】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038709. |
| 【4】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038710. |
| 【5】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038711. |
| 【6】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038712. |
| 【7】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038716. |
| 【8】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038717. |
| 【2】 Chen, K., Risatti, C., Bultman, M. et al. Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS-663068. J Org Chem 2014, 79(18): 8757-67. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (XV) | 67610 | 1-(phenylsulfonyl)pyrrole;N-(Benzenesulfonyl)pyrrole;N-Phenylsulfonylpyrrole;1-(Benzenesulfonyl)-1H-pyrrole | 16851-82-4 | C10H9NO2S | 详情 | 详情 |
| (XVI) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XVII) | 67611 | 2-chloro-1-[1-(phenylsulfonyl)pyrrol-3-yl]ethanone | C12H10ClNO3S | 详情 | 详情 | |
| (XVIII) | 67612 | sodium N-tosyl formamide | C8H8NNaO3S | 详情 | 详情 | |
| (XIX) | 59937 | 4-methylbenzenesulfonamide | 70-55-3 | C7H9NO2S | 详情 | 详情 |
| (XX) | 67613 | sodium tosylamide | C7H8NNaO2S | 详情 | 详情 | |
| (XXI) | 67614 | N-(2-oxo-2-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)ethyl)-N-tosylformamide | C20H18N2O6S2 | 详情 | 详情 | |
| (XXII) | 67615 | 4-methyl-N-((2-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-1,3-dioxolan-2-yl)methyl)benzenesulfonamide | C21H22N2O6S2 | 详情 | 详情 | |
| (XXIII) | 67616 | 1-(phenylsulfonyl)-6-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4(5H)-one | C20H18N2O5S2 | 详情 | 详情 | |
| (XXIV) | 67617 | 4-methoxy-1-(phenylsulfonyl)-6-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine | C21H20N2O5S2 | 详情 | 详情 | |
| (XXV) | 67618 | 4-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine | C14H12N2O3S | 详情 | 详情 | |
| (XXVI) | 67619 | 4-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine 6-oxide | C14H12N2O4S | 详情 | 详情 | |
| (XXVII) | 67620 | 7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine hydrochloride hydrate | C8H7BrN2O.HCl.H2O | 详情 | 详情 | |
| (XXVIII) | 67621 | methyl 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate | C11H9BrN2O4 | 详情 | 详情 | |
| (XXIX) | 67622 | 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid hydrobromide | C10H7BrN2O4.HBr | 详情 | 详情 |