Z4349

Z4349
Identifiers
	IUPAC name (5S)-5-[(1S)-2-[bis[(2R)-butan-2-yl]amino]-1-hydroxyethyl]-1-(2-chlorobenzyl)pyrrolidin-2-one;
CAS Number	127093-63-4;
PubChem CID	10317679;
ChemSpider	8493143;
Chemical and physical data
Formula	C21H33ClN2O2
Molar mass	380.96 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC[C@@H](C)N(C[C@@H]([C@@H]1CCC(=O)N1CC2=CC=CC=C2Cl)O)[C@H](C)CC;
	InChI InChI=1S/C21H33ClN2O2/c1-5-15(3)23(16(4)6-2)14-20(25)19-11-12-21(26)24(19)13-17-9-7-8-10-18(17)22/h7-10,15-16,19-20,25H,5-6,11-14H2,1-4H3/t15-,16-,19+,20+/m1/s1; Key:YNGZJSALRCLELM-YKCBXCCJSA-N;

Z4349 is an opioid analgesic drug developed in the 1990s by the pharmaceutical company Zambon. It is a derivative of an older drug viminol, which has been modified to improve potency and metabolic stability. In tests on mice it was found to be several hundred times the potency of morphine.^[1]^[2]

Synthesis

Esterification of L-glutamic acid [56-86-0] (1) with ethanol gives Glutamic acid diethyl ester [16450-41-2] (2). Lactam formation occurs on heating to give L-Pyroglutamic acid ethyl ester [7149-65-7] (3). The reduction of the ester with sodium borohydride gives L-Pyroglutaminol [17342-08-4] (4). Treatment with methyl chloride gave (S)-(5-Oxopyrrolidin-2-yl)methyl methanesulfonate [93288-20-1] (5). Displacement of the leaving group with cyanide led to (S)-5-Oxo-2-pyrrolidineacetonitrile [72479-06-2] (6). Catalytic reduction over Rosenmund catalyst in the presence of dimethylamine led to (5S)-5-[2-(dimethylamino)ethyl]pyrrolidin-2-one, PC13306712 (7). Oxidation in the presence of hydrogen peroxide formed the N-oxide (8). Elimination of the amino group in the presence of weak base led to (S)-5-Vinylpyrrolidin-2-one [93288-23-4] (9). Alkylation of the amino group with 2-Chlorobenzyl chloride [611-19-8] (10) in the presence of sodium hydride base led to (5S)-1-[(2-chlorophenyl)methyl]-5-ethenylpyrrolidin-2-one, PC56976994 (11). Treatment of the vinyl group with peroxy acid gave the oxirane. (5S)-1-[(2-chlorophenyl)methyl]-5-(oxiran-2-yl)pyrrolidin-2-one, PC88496451 (12). Treatment with (2R)-N-[(2R)-butan-2-yl]butan-2-amine, PC6347588 (13) completed the synthesis of Z4349 (14).

References

^ US 4960788, Carenzi A, Chiarino D, Bella DD, Grancini GC, Veneziani C, "Pyrrolidone-2 compounds and their use for central analgesic activity", issued 2 October 1990, assigned to Zambon Group S.P.A.
^ Napoletano M, Delia BD, Fraire C, Grancini G, Masotto C, Ricciardi S, Zambon C (1995). "Stereoselective synthesis and evaluation of all stereoisomers of Z4349, a novel and selective μ-opioid analgesic". Bioorganic & Medicinal Chemistry Letters. 5 (6): 589–592. doi:10.1016/0960-894X(95)00077-7.

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[1] US 4960788, Carenzi A, Chiarino D, Bella DD, Grancini GC, Veneziani C, "Pyrrolidone-2 compounds and their use for central analgesic activity", issued 2 October 1990, assigned to Zambon Group S.P.A.

[2] Napoletano M, Delia BD, Fraire C, Grancini G, Masotto C, Ricciardi S, Zambon C (1995). "Stereoselective synthesis and evaluation of all stereoisomers of Z4349, a novel and selective μ-opioid analgesic". Bioorganic & Medicinal Chemistry Letters. 5 (6): 589–592. doi:10.1016/0960-894X(95)00077-7.

[1]

[2]

Synthesis

See also

References