ethyl 2-chloro-3-oxopropanoate -Drug Synthesis Database

【结构式】

【分子编号】16600

【品名】ethyl 2-chloro-3-oxopropanoate

【CA登记号】

【分子式】C₅H₇ClO₃

【分子量】150.56148

【元素组成】C 39.89% H 4.69% Cl 23.55% O 31.88%

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：(XVI)

The thiazolyl carbonate (XI) has been synthesized as follows: The reaction of formamide (XIV) with P2S5 in ethyl ether gives thioformamide (XV), which is cyclized with 2-chloro-3-oxopropionic acid ethyl ester (XVI) [obtained by condensation of ethyl chloroacetate (XVII) with ethyl formate (XVIII) by means of t-BuOK in THF] yielding thiazol-5-carboxylic acid ethyl ester (XIX). The reduction of (XIX) with LiAlH4 in THF affords 5-thiazolylmethanol (XX), which is then esterified with 4-nitrophenyl chloroformate (XXI) by means of 4-methylmorpholine (MPH) in dichloromethane to give the desired product (XI).

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700.
【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 .
【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 .
【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35.

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)	16595	4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate	144163-97-3	C₁₁H₈N₂O₅S	详情	详情
(XIV)	16598	Formamide	75-12-7	CH₃NO	详情	详情
(XV)	16599	Thioformamide		CH₃NS	详情	详情
(XVI)	16600	ethyl 2-chloro-3-oxopropanoate		C₅H₇ClO₃	详情	详情
(XVII)	16601	ethyl chloroacetate; ethyl 2-chloroacetate	105-39-5	C₄H₇ClO₂	详情	详情
(XVIII)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(XIX)	16603	ethyl 1,3-thiazole-5-carboxylate	32955-22-9	C₆H₇NO₂S	详情	详情
(XX)	16604	1,3-thiazol-5-ylmethanol;5-thiazolylmethanol;Thiazole-5-methanol	38585-74-9	C₄H₅NOS	详情	详情
(XXI)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of ethyl chloroacetate (I) with ethyl formate (II) by means of potassium tert-butoxide in diisopropyl ether gives the 2-formylchloroacetate (III), which is cyclized with 6-methylpyridine-2-amine (IV) by means of conc. H2SO4, yielding 5-methylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (V). The chlorination of (V) with NCS in THF affords the chloromethyl derivative (VI), which is condensed with the monoprotected diamine (VII) by means of TEA to provide the adduct (VIII). The cyclization of (VIII) by means of NaOMe, TEA and NaI in DMF gives 4-[4-(benzyloxycarbonylamino)butyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one (IX), which is deprotected with H2 over Pd/C in MeOH, yielding the butylamine derivative (X). Finally, this compound is sulfonated with N-phenyltrifluoromethylsulfonimide (XI) and TEA in DMF.

参考文献中间体

合成目标

【1】 Ikemoto, T.; et al.; A practical synthesis of the chronic renal disease agent, 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives, using regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxy with N-chlorosuccinimide. Tetrahedron 2000, 56, 40, 7915.
【2】 Takatani, M.; Shibouta, Y.; Tomimatsu, K.; Kawamoto, T. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0771319; JP 1996081467; WO 9602542 .

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)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情
(II)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(III)	16600	ethyl 2-chloro-3-oxopropanoate		C₅H₇ClO₃	详情	详情
(IV)	19678	6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine	1824-81-3	C₆H₈N₂	详情	详情
(V)	42075	ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate		C₁₁H₁₂N₂O₂	详情	详情
(VI)	42076	ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate		C₁₁H₁₁ClN₂O₂	详情	详情
(VII)	42077	benzyl 4-aminobutylcarbamate	62146-62-7	C₁₂H₁₈N₂O₂	详情	详情
(VIII)	42078	ethyl 5-[[(4-[[(benzyloxy)carbonyl]amino]butyl)amino]methyl]imidazo[1,2-a]pyridine-3-carboxylate		C₂₃H₂₈N₄O₄	详情	详情
(IX)	42079	benzyl 4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-4-yl)butylcarbamate		C₂₁H₂₂N₄O₃	详情	详情
(X)	42080	4-(4-aminobutyl)-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one		C₁₃H₁₆N₄O	详情	详情
(XI)	17573	N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide	37595-74-7	C₈H₅F₆NO₄S₂	详情	详情

Extended Information