ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate -Drug Synthesis Database

【结构式】

【分子编号】16723

【品名】ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate

【CA登记号】

【分子式】C₂₅H₂₆ClNO₂

【分子量】407.93968

【元素组成】C 73.61% H 6.42% Cl 8.69% N 3.43% O 7.84%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

The cyclization of 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole (I) with 4-chlorophenacyl bromide (II) ethyl ether/ethanol gives 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (III), which is condensed with ethyl diazoacetate (IV) by means of copper powder in refluxing toluene to afford 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid ethyl ester (V). Finally, this ester is hydrolyzed with NaOH in ethanol/water.

参考文献中间体

合成目标

【1】 Rabasseda, X.; Mealy, N.; Castañer, J.; ML-3000. Drugs Fut 1995, 20, 10, 1007.
【2】 Augustin, J.; Kiefer, W.; Dannhardt, G.; Laufer, S.A.; (6,7-Diaryldihydropyrrolizin-5-yl)acetic acids, a novel class of potent dual inhibitors of both cyclooxygenase and 5-lipoxygenase. J Med Chem 1994, 37, 12, 1894-7.

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)	16719	5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole	116673-95-1	C₁₃H₁₇N	详情	详情
(II)	16720	2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone	536-38-9	C₈H₆BrClO	详情	详情
(III)	16721	6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine		C₂₁H₂₀ClN	详情	详情
(IV)	15911	Ethyldiazoacetate; ethyl 2-diazoacetate	623-73-4	C₄H₆N₂O₂	详情	详情
(V)	16723	ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate		C₂₅H₂₆ClNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

A new synthesis of ML-3000 has been published: The reaction of 3-phenyl-2-propynyl chloride (I) with isobutyraldehyde (II) by means of tetrabutylammonium iodide/NaI/NaOH in toluene/water gives 2,2-dimethyl-5-phenyl-4-pentynal (III), which is condensed with glycine methyl ester by means of NaBH(OAc)3 and triethylamine in dichloromethane yielding the N-alkyl-glycine (V). The cyclization of (V) by means of pivalic acid at 150 C affords the bicyclic ketone (VI), which is condensed with diethyl oxalate (VII) by means of sodium ethoxide in ethanol giving the ethoxalyl derivative (VIII). The esterification of (VIII) with the triflic amide (IX) yields the triflate (X), which is condensed with 4-chlorophenylboronic acid (XI) by means of palladium tetrakis(triphenylphosphine) as catalyst in refluxing THF affording the compound (XII). The reduction of the oxoacetic group with tosyl hydrazide (XIII) in refluxing ethanol gives the expected acetate derivative (XIV), which is finally hydrolyzed with NaOH in hot ethanol/water.

参考文献中间体

合成目标

【1】 Cossy, J.; Belotti, D.; Synthesis of ML-3000, an inhibitor of cyclooxygenase and 5-lipoxygenase. J Org Chem 1997, 62, 23, 7900.

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)	17565	1-(3-chloro-1-propynyl)benzene		C₉H₇Cl	详情	详情
(II)	13226	2-Methylpropanal; Isobutyraldehyde	78-84-2	C₄H₈O	详情	详情
(III)	17567	2,2-dimethyl-5-phenyl-4-pentynal		C₁₃H₁₄O	详情	详情
(IV)	17568	methyl 2-aminoacetate		C₃H₇NO₂	详情	详情
(V)	17569	methyl 2-[(2,2-dimethyl-5-phenyl-4-pentynyl)amino]acetate		C₁₆H₂₁NO₂	详情	详情
(VI)	17570	2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-6(5H)-one		C₁₅H₁₇NO	详情	详情
(VII)	17571	Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate	95-92-1	C₆H₁₀O₄	详情	详情
(VIII)	17572	ethyl 2-(6-hydroxy-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate		C₁₉H₂₁NO₄	详情	详情
(IX)	17573	N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide	37595-74-7	C₈H₅F₆NO₄S₂	详情	详情
(X)	17574	ethyl 2-(2,2-dimethyl-7-phenyl-6-[[(trifluoromethyl)sulfonyl]oxy]-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate		C₂₀H₂₀F₃NO₆S	详情	详情
(XI)	17575	4-chlorophenylboronic acid	1679-18-1	C₆H₆BClO₂	详情	详情
(XII)	17576	ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetate		C₂₅H₂₄ClNO₃	详情	详情
(XIII)	17577	p-Toluenesulfonyl Hydrazide; 4-methylbenzenesulfonohydrazide	1576-35-8	C₇H₁₀N₂O₂S	详情	详情
(XIV)	16723	ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate		C₂₅H₂₆ClNO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

An alternative route to improve the yield of a previous reported synthesis of ML-3000 [Cossy, J. and Belotti, D. J Org Chem 1997, 62(23): 7900] has been reported: The reduction of the oxoacetic ester intermediate (I) can also be performed stepwise by treatment of (I) with tosylhydrazine (II), isolation of the corresponding tosylhydrazone (III), and reduction with sodium cyanoborohydride in ethanol to yield the expected acetate (IV). Finally, this compound is hydrolyzed with NaOH as already described.

参考文献中间体

合成目标

【1】 Cossy, J.; Belotti, D.; Synthetic studies towards ML-3000 - A concise synthesis of this non-steroidal anti-inflammatory drug. Tetrahedron 1999, 55, 16, 5145.

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)	17576	ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetate		C₂₅H₂₄ClNO₃	详情	详情
(II)	17577	p-Toluenesulfonyl Hydrazide; 4-methylbenzenesulfonohydrazide	1576-35-8	C₇H₁₀N₂O₂S	详情	详情
(III)	28699	ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-[(Z)-2-[(4-methylphenyl)sulfonyl]hydrazono]acetate		C₃₂H₃₂ClN₃O₄S	详情	详情
(IV)	16723	ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate		C₂₅H₂₆ClNO₂	详情	详情

Extended Information