MLN-519, LDP-519, PS-519, -Drug Synthesis Database

【结构式】

【药物名称】MLN-519, LDP-519, PS-519

【化学名称】(1R,4R,5S)-1-[1(S)-Hydroxy-2-methylpropyl]-4-propyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione

【CA登记号】211866-70-5

【分子式】C₁₂H₁₉NO₄

【分子量】241.28953

【开发单位】Millennium (Originator), PAION (Licensee)

【药理作用】Antipsoriatics, Cerebrovascular Diseases, Treatment of, DERMATOLOGIC DRUGS, Immunologic Neuromuscular Disorders, Treatment of, IMMUNOMODULATING AGENTS, Ischemic Stroke, Treatment of, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, Stroke, Treatment of, Treatment of Transplant Rejection, Proteasome Inhibitor

合成路线1 合成路线2 合成路线3

合成路线1

The intermediate (R)-formyl amide (IX) was synthesized as follows. Acylation of the lithium anion of (S)-4-benzyl-2-oxazolidinone (I) with valeryl chloride (II) provided acyl oxazolidinone (III). Subsequent diastereoselective benzyloxymethylation of (III) with chloride (IV) and TiCl4 gave benzyl ether (V). Hydrolysis of (V) with lithium peroxide, followed by coupling of the resulting carboxylic acid (VI) with diethylamine in the presence of TBTU yielded diethylamide (VII). Hydrogenolysis of the benzyl group of (VII) using Pearlman's catalyst afforded alcohol (VIII), which was oxidized to aldehyde (IX) by means of Dess-Martin periodinane or NaOCl in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) to give (IX).

参考文献中间体

【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967.
【2】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 .
【3】 Plamondon, L.; Adams, J.; Elliot, P. (ProScript, Inc.); Proteasome inhibitors, ubiquitin pathway inhibitors or agents that interfere with the activation of NF-kappaB via the ubiquitin proteasome pathway to treat inflammatory and autoimmune diseases. WO 9915183 .

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)	14694	(S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone	90719-32-7	C₁₀H₁₁NO₂	详情	详情
(II)	15116	pentanoyl chloride; valeryl chloride	638-29-9	C₅H₉ClO	详情	详情
(III)	29431	(4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one		C₁₅H₁₉NO₃	详情	详情
(IV)	14560	Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene	3587-60-8	C₈H₉ClO	详情	详情
(V)	37794	(4S)-4-benzyl-3-[(2R)-2-[(benzyloxy)methyl]pentanoyl]-1,3-oxazolidin-2-one		C₂₃H₂₇NO₄	详情	详情
(VI)	37795	(2R)-2-[(benzyloxy)methyl]pentanoic acid		C₁₃H₁₈O₃	详情	详情
(VII)	37796	(2R)-2-[(benzyloxy)methyl]-N,N-diethylpentanamide		C₁₇H₂₇NO₂	详情	详情
(VIII)	37797	(2R)-N,N-diethyl-2-(hydroxymethyl)pentanamide		C₁₀H₂₁NO₂	详情	详情
(IX)	37798	(2R)-N,N-diethyl-2-formylpentanamide		C₁₀H₁₉NO₂	详情	详情

合成路线2

On the other hand, Wittig condensation of isobutyraldehyde (X) with methyl (triphenylphosphoranylidene)acetate (XI) afforded (E)-4-methylpent-2-enoic acid methyl ester (XII). Sharpless catalytic asymmetric dihydroxylation of (XII) gave diol (XIII). Condensation of diol (XIII) with trimethyl orthobenzoate in the presence of BF3.Et2O, followed by treatment of the crude cyclic orthoester with acetyl bromide produced bromo ester (XIV). The required alpha-amino group was then introduced by nucleophilic displacement of the bromide of (XIV) with NaN3 in DMSO, followed by catalytic hydrogenation of the resulting azide (XV). The intermediate amino ester (XVI) was then rearranged to hydroxy amide (XVII) upon refluxing in EtOAc. Cyclization of (XVII) to the required trans oxazoline (XVIII) was then achieved by treatment with p-toluenesulfonic acid in boiling toluene.

参考文献中间体

【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967.
【2】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	13226	2-Methylpropanal; Isobutyraldehyde	78-84-2	C₄H₈O	详情	详情
(XI)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(XII)	37799	methyl (E)-4-methyl-2-pentenoate		C₇H₁₂O₂	详情	详情
(XIII)	37800	methyl (2S,3R)-2,3-dihydroxy-4-methylpentanoate		C₇H₁₄O₄	详情	详情
(XIV)	37801	(1S,2S)-2-bromo-1-isopropyl-3-methoxy-3-oxopropyl benzoate		C₁₄H₁₇BrO₄	详情	详情
(XV)	37802	(1S,2R)-2-azido-1-isopropyl-3-methoxy-3-oxopropyl benzoate		C₁₄H₁₇N₃O₄	详情	详情
(XVI)	37803	(1S,2R)-2-amino-1-isopropyl-3-methoxy-3-oxopropyl benzoate		C₁₄H₁₉NO₄	详情	详情
(XVII)	37804	methyl (2R,3S)-2-(benzoylamino)-3-hydroxy-4-methylpentanoate		C₁₄H₁₉NO₄	详情	详情
(XVIII)	37805	methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate		C₁₄H₁₇NO₃	详情	详情

合成路线3

Treatment of the lithium enolate of oxazoline ester (XVIII) with dimethylaluminum chloride, followed by aldol condensation with aldehyde (IX) at -80 C diastereoselectively led to adduct (XIX). Hydrogenolysis of the oxazoline (XIX) with concomitant cyclization of the intermediate aminodiol produced lactam (XX). The methyl ester group of (XX) was then hydrolyzed with NaOH to give hydroxyacid (XXI). This was finally cyclized to the title lactone employing either TBTU or isopropenyl chloroformate in the presence of Et3N.

参考文献中间体

【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967.
【2】 Plamondon, L.; Adams, J.; Elliot, P. (ProScript, Inc.); Proteasome inhibitors, ubiquitin pathway inhibitors or agents that interfere with the activation of NF-kappaB via the ubiquitin proteasome pathway to treat inflammatory and autoimmune diseases. WO 9915183 .
【3】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	37798	(2R)-N,N-diethyl-2-formylpentanamide	C₁₀H₁₉NO₂	详情	详情
(XVIII)	37805	methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate	C₁₄H₁₇NO₃	详情	详情
(XIX)	37806	methyl (4S,5S)-4-[(1S,2R)-2-[(diethylamino)carbonyl]-1-hydroxypentyl]-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate	C₂₄H₃₆N₂O₅	详情	详情
(XX)	37807	methyl (2R,3S,4R)-3-hydroxy-2-[(1R)-1-hydroxy-2-methylpropyl]-5-oxo-4-propyl-2-pyrrolidinecarboxylate	C₁₃H₂₃NO₅	详情	详情
(XXI)	37808	(2R,3S,4R)-3-hydroxy-2-[(1R)-1-hydroxy-2-methylpropyl]-5-oxo-4-propyl-2-pyrrolidinecarboxylic acid	C₁₂H₂₁NO₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)