2-chloro-5-nitropyridine -Drug Synthesis Database

【结构式】

【分子编号】29610

【品名】2-chloro-5-nitropyridine

【CA登记号】4548-45-2

【分子式】C₅H₃ClN₂O₂

【分子量】158.5438

【元素组成】C 37.88% H 1.91% Cl 22.36% N 17.67% O 20.18%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XI)

Coupling of 3-hydroxypyridine (X) with 2-chloropyridine (XI) afforded the corresponding dipyridyl ether (XII). After reduction of the nitro group of (XII) with SnCl2, the resulting aminopyridine (XIII) was treated with phenyl chloroformate to give the phenyl carbamate (XIV). Finally, condensation of carbamate (XIV) with indoline (IX) produced the title carboxamide.

参考文献中间体

合成目标

【1】 Bromidge, S.M.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. useful as 5-HT-2C receptor antagonists. EP 0912554; WO 9748699 .
【2】 Blackburn, T.P. (SmithKline Beecham plc); Pharmaceutical compsn. containing a 5HT2C antagonist and a D2 antagonist. WO 9804289 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	29608	5-methyl-6-(trifluoromethyl)indoline		C₁₀H₁₀F₃N	详情	详情
(X)	29609	2-methyl-3-pyridinol	1121-25-1	C₆H₇NO	详情	详情
(XI)	29610	2-chloro-5-nitropyridine	4548-45-2	C₅H₃ClN₂O₂	详情	详情
(XII)	29611	2-methyl-3-[(5-nitro-2-pyridinyl)oxy]pyridine; 2-methyl-3-pyridinyl 5-nitro-2-pyridinyl ether		C₁₁H₉N₃O₃	详情	详情
(XIII)	29612	6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinamine; 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylamine		C₁₁H₁₁N₃O	详情	详情
(XIV)	29613	phenyl 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylcarbamate		C₁₈H₁₅N₃O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Coupling between 2-chloro-5-nitropyridine (I) and 4-nitrophenol (II) affords the diaryl ether (III). Subsequent catalytic hydrogenation of both nitro groups of (III) gives rise to diamine (IV). This is finally acylated with (S)-2,2-dimethylcyclopropanecarbonyl chloride (V) to furnish the title diamide.

参考文献中间体

合成目标

【1】 Yamamoto, T.; Iino, Y.; Kobayashi, T.; Fujita, K.; Hatanaka, T.; Kodaira, A.; Takehana, K.; Konishi, A. (Ajinomoto Co., Inc.); Heterocyclic cpds. and medicinal use thereof. EP 1193255; WO 0102359 .

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)	29610	2-chloro-5-nitropyridine	4548-45-2	C₅H₃ClN₂O₂	详情	详情
(II)	11236	4-Nitrophenol; p-Nitrophenol	100-02-7	C₆H₅NO₃	详情	详情
(III)	57425	4-nitrophenyl 5-nitro-2-pyridinyl ether; 5-nitro-2-(4-nitrophenoxy)pyridine		C₁₁H₇N₃O₅	详情	详情
(IV)	57426	6-(4-aminophenoxy)-3-pyridinamine; 6-(4-aminophenoxy)-3-pyridinylamine		C₁₁H₁₁N₃O	详情	详情
(V)	57427	(1S)-2,2-dimethylcyclopropanecarbonyl chloride		C₆H₉ClO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Coupling of 2-chloro-5-nitropyridine (II) with the sodium alkoxide of 5-methyl-2-phenylisoxazol-4-ylmethanol (I) gave the 2-alkoxy-5-nitropyridine (III), which was reduced to the aminopyridine (IV) by catalytic hydrogenation over Pd/C. Meerwein arylation of methyl acrylate with the diazonium salt generated from amine (IV) furnished the bromopropionate (V), which was further dehydrohalogenated in the presence of DBU to the pyridyl acrylate (VI). Ester reduction in (VI) employing DIBAL yielded the allylic alcohol (VII). This was hydrogenated to the saturated alcohol (VIII) in the presence of Pd/C. After activation of alcohol (VIII) as the corresponding mesylate (IX), displacement by KCN in hot DMF yielded nitrile (X). This was finally converted to the desired tetrazole by treatment with sodium azide and ammonium chloride.

参考文献中间体

合成目标

【1】 Momose, Y.; Ikeda, H.; Odaka, H.; Maekawa, T.; Sohda, T.; Novel 5-substituted-1H-tetrazole derivatives as potent glucose and lipid lowering agents. Chem Pharm Bull 2002, 50, 1, 100.
【2】 Sohda, T.; Ikeda, H.; Momose, Y. (Takeda Chemical Industries, Ltd.); Tetrazole derivs., their production and use. CA 2125549; EP 0629624; JP 1995053555; US 5591862 .

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)	55939	(5-methyl-2-phenyl-1,3-oxazol-4-yl)methanol	70502-03-3	C₁₁H₁₁NO₂	详情	详情
(II)	29610	2-chloro-5-nitropyridine	4548-45-2	C₅H₃ClN₂O₂	详情	详情
(III)	55940	(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl 5-nitro-2-pyridinyl ether; 2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-5-nitropyridine		C₁₆H₁₃N₃O₄	详情	详情
(IV)	55941	6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinamine; 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinylamine		C₁₆H₁₅N₃O₂	详情	详情
(V)	55942	methyl 2-bromo-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}propanoate		C₂₀H₁₉BrN₂O₄	详情	详情
(VI)	55943	methyl (E)-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-2-propenoate		C₂₀H₁₈N₂O₄	详情	详情
(VII)	55944	(E)-3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-2-propen-1-ol		C₁₉H₁₈N₂O₃	详情	详情
(VIII)	55945	3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}-1-propanol		C₁₉H₂₀N₂O₃	详情	详情
(IX)	55946	3-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}propyl methanesulfonate		C₂₀H₂₂N₂O₅S	详情	详情
(X)	55947	4-{6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-pyridinyl}butanenitrile		C₂₀H₁₉N₃O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Condensation of 2-chloro-5-nitropyridine (I) with cis-2,6-dimethylmorpholine (II) by means of K2CO3 in DMF at 50 °C gives intermediate (III), which is hydrogenated with H2 over Pd/C in MeOH to yield amine (IV) . Coupling of amine (IV) with 3-bromo-4-methylbenzoic acid (V) using HATU and Et3N or DIEA in DMF affords the corresponding amide (VI), which is finally submitted to Suzuki coupling with 4-(trifluoromethoxy)phenyl boronic acid (VII) in the presence of Pd(PPh3)4 and Na2CO3 in toluene/EtOH/H2O , DME or DME/H2O at 135 °C.
Alternatively, Suzuki coupling of 3-bromo-4-methylbenzoic acid (V) with 4-(trifluoromethoxy)phenylboronic acid (VII) in the presence of Pd(PPh3)4 and Na2CO3 in DME/H2O gives intermediate (IX), which is finally coupled with amine (IV) using HATU and Et3N in DMF .

参考文献中间体

合成目标

【1】 gao, W., Jiang, J., Wan, Y., Cheng, D., Han, D., Wu, X., Pan, S. (IRM, LLC). Compounds and compositions as hedgehog pathway modulators. CN 102746285, EP 2021328, EP2363393, JP 2009536220, US 2009203666, US 8178563, US 2012196849, WO 2007131201.
【2】 Dierks, C., Warmuth, M., Wu, X. (IRM, LLC). Biphenylcarboxamide derivatives as hedgehog pathway modulators. CN 101820950, EP 2162190, JP 2010529963, US 2010197659, WO 2008154259.
【3】 Fritze, E., Corcelle, K., grubesa, M.E. (Novartis Ag). Pharmaceutical compositions. CN 102481249, CN 103893184, EP 2456422, JP 2012533598, KR 2012097482, US 2012122866, US 8722672, WO 2011009852.
【4】 Pan, S., Wu, X., Jiang, J. et al. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS Med Chem Lett 2010, 1(3): 130-4.

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)	29610	2-chloro-5-nitropyridine	4548-45-2	C₅H₃ClN₂O₂	详情	详情
(II)	37122	(2R,6S)-2,6-dimethylmorpholine；cis-2,6-dimethylmorpholine	6485-55-8	C₆H₁₃NO	详情	详情
(III)	67845	(2R,6S)-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine		C₁₁H₁₅N₃O₃	详情	详情
(IV)	67844	6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-amine		C₁₁H₁₇N₃O	详情	详情
(V)	67847	3-bromo-2-methylbenzoic acid	76006-33-2	C₈H₇BrO₂	详情	详情
(VI)	67846	3-bromo-N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methylbenzamide		C₁₉H₂₂BrN₃O₂	详情	详情
(VII)	67849	4-(trifluoromethoxy)phenyl boronic acid	139301-27-2	C₇H₆BF₃O₃	详情	详情
(VIII)	67848	N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide		C₂₆H₂₆F₃N₃O₃	详情	详情
(IX)	67850	2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxylic acid		C₁₅H₁₁F₃O₃	详情	详情

Extended Information