3-methyl-1,2,4-triazole；3-Methyltriazole；3-Methyl-1H-1,2,4-triazole；3-Methyl-4H-1,2,4-triazole -Drug Synthesis Database

【结构式】

【分子编号】67601

【品名】3-methyl-1,2,4-triazole；3-Methyltriazole；3-Methyl-1H-1,2,4-triazole；3-Methyl-4H-1,2,4-triazole

【CA登记号】7170-01-6

【分子式】C₃H₅N₃

【分子量】83.09292

【元素组成】C 43.36% H 6.07% N 50.57%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

Cyclocondensation of formic hydrazide (I) with thioacetamide (II) at 150 °C gives 3-methyl-1,2,4-triazole (III), which by condensation with 7-chloro-4-methoxy-pyrrolo[2,3-c]pyridine (IV) in the presence of CuI and K2CO3 at 173 °C provides 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine (V). Friedel-Crafts acylation of compound (V) with methyl chloro(oxo)acetate (VI) using AlCl3 in CH2Cl2/MeNO2 affords the keto ester (VII), which is hydrolyzed using NaOH in MeOH to yield the carboxylic acid (VIII). Condensation of acid (VIII) with 1-benzoylpiperazine (IX) by means of EDC and Et3N in DMF gives piperazinamide (X). Treatment of intermediate (X) with NaH and I2 in THF followed by N-alkylation of di-tert-butyl chloromethyl phosphate (XI) (obtained by the chloromethylation of the tetrabutylammonium salt of di-tert-butyl hydrogen phosphate (XII) with chloroiodomethane (XIII) optionally in benzene) in acetone/H2O, or the direct condensation of intermediate (X) with chloromethyl phosphate (XI) in the presence of CsCO3 and KI in NMP affords the di-tert-butyl phosphate ester (XIV). Finally, O-deprotection of intermediate (XIV) is performed by treatment with TFA in CH2Cl2, or by heating in acetone/H2O at 40 °C .

参考文献中间体

合成目标

【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.

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)	15486	formic hydrazide; Formylhydrazine	624-84-0	CH₄N₂O	详情	详情
(II)	19170	ethanethioamide	62-55-5	C₂H₅NS	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
(IV)	67602	7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridine		C₈H₇ClN₂O	详情	详情
(V)	67603	4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine		C₁₁H₁₁N₅O	详情	详情
(VI)	26971	2-methoxy-2-oxoacetyl chloride	5781-53-3	C₃H₃ClO₃	详情	详情
(VII)	67604	methyl 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate		C₁₄H₁₃N₅O₄	详情	详情
(VIII)	67605	2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid		C₁₃H₁₁N₅O₄	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
(X)	67607	1-(4-benzoylpiperazin-1-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione		C₂₄H₂₃N₇O₄	详情	详情
(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
(XII)	67608	tetra-tert-butylammonium di-tert-butyl phosphate		C₈H₁₈O₄P.C₁₆H₃₆N	详情	详情
(XIII)	42238	chloro(iodo)methane	593-71-5	CH₂ClI	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

合成路线2

该中间体在本合成路线中的序号：(III)

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 .

参考文献中间体

合成目标

【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

Extended Information