Licofelone, ML-3000, -Drug Synthesis Database

【结构式】

【药物名称】Licofelone, ML-3000

【化学名称】2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid

【CA登记号】156897-06-2

【分子式】C₂₃H₂₂ClNO₂

【分子量】379.89029

【开发单位】EuroAlliance (Originator), Merckle (Originator)

【药理作用】Antiarthritic Drugs, Osteoarthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, 5-Lipoxygenase Inhibitors, Cyclooxygenase-1 Inhibitors, Cyclooxygenase-2 Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

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

【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

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

【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

The synthesis of the acyl glucuronide of ML-3000 has been described: The cleavage of the lactone ring of D-glucuronic acid gamma-lactone (I) gives the bromide derivative (II), which is treated with silver oxide and benzyl alcohol to yield compound (III). The methanolysis of (III) with sodium methoxide in methanol, followed by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords silylated compound (IV). The hydrolysis of the ester group of (IV) with NaOH in THF/water, followed by reesterification with diethyl chlorophosphate, 2,2,2-trichloroehanol and DMAP gives the silylated trichloroethyl ester (V), which is debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate yielding D-glucuronate (VI). The esterification of the acid group of ML-3000 (VII) with (VI) by means of triphenylphosphine and DIAD in THF affords the corresponding ester (VIII), which is finally deprotected first with Zn and KH2PO4 to eliminate the trichloroethyl group, and then with THF in acetonitrile to eliminate the silyl groups. The product wasisolated as a 1:2 mixture of the alpha- and beta-anomers.

参考文献中间体

【1】 Ries, M.; Kirschning, A.; Albrecht, W.; Domann, S.; Arnold, P.; Laufer, S.; Martin, W.; Synthesis and biological identification of the acyl glucuronide of the antiinflammatory drug ML-3000. Bioorg Med Chem Lett 1997, 7, 7, 903.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17579	(1S,2R,3S,4R,5S)-2,3-bis(acetoxy)-7-oxo-6,8-dioxabicyclo[3.2.1]oct-4-yl acetate	C₁₂H₁₄O₉	详情	详情
(II)	17580	methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate	C₁₃H₁₇BrO₉	详情	详情
(III)	17581	methyl (2S,3R,4S,5R,6R)-3,4,5-tris(acetoxy)-6-(benzyloxy)tetrahydro-2H-pyran-2-carboxylate	C₂₀H₂₄O₁₀	详情	详情
(IV)	17582	methyl (2S,3R,4S,5R,6R)-6-(benzyloxy)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-carboxylate	C₃₂H₆₀O₇Si₃	详情	详情
(V)	17583	2,2,2-trichloroethyl (2S,3R,4S,5R,6R)-6-(benzyloxy)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-carboxylate	C₃₃H₅₉Cl₃O₇Si₃	详情	详情
(VI)	17584	2,2,2-trichloroethyl (2S,3R,4S,5R)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxytetrahydro-2H-pyran-2-carboxylate	C₂₆H₅₃Cl₃O₇Si₃	详情	详情
(VII)	17585	2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid	C₂₃H₂₂ClNO₂	详情	详情
(VIII)	17586	2,2,2-trichloroethyl (2S,3R,4S,5R)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]-6-([2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetyl]oxy)tetrahydro-2H-pyran-2-carboxylate	C₄₉H₇₃Cl₄NO₈Si₃	详情	详情

合成路线4

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

【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

合成路线5

The cyclization of 4-chloro-3,3-dimethylbutyronitrile (I) with benzylmagnesium chloride (II) in ethyl ether containing some iodine gives 2-benzyl-4,4-dimethyl-1-pyrroline (III), which is cyclized with 4'-chlorophenacyl bromide (IV) by means of NaHCO3 in methanol, yielding 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro.1H-pyrrolizine (V). The condensation of (V) with oxalyl chloride (VI) in THF affords 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetyl chloride (VII), which is finally reduced and hydrolyzed with hydrazine in hot diethyleneglycol to provide the target licofelone.

参考文献中间体

【1】 Laufer, S.; Striegel, H.-G.; Kammermeier, T.; Merckle, P. (Merckle GmbH); Method for producing 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl acetic acid. US 6417371; WO 0155149 .

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)	60052	4-chloro-3,3-dimethylbutanenitrile		C₆H₁₀ClN	详情	详情
(II)	18327	benzyl(chloro)magnesium	6921-34-2	C₇H₇ClMg	详情	详情
(III)	16719	5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole	116673-95-1	C₁₃H₁₇N	详情	详情
(IV)	16720	2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone	536-38-9	C₈H₆BrClO	详情	详情
(V)	16721	6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine		C₂₁H₂₀ClN	详情	详情
(VI)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(VII)	60053	2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetyl chloride		C₂₃H₁₉Cl₂NO₂	详情	详情

Extended Information