JTP-4819, -Drug Synthesis Database

【结构式】

【药物名称】JTP-4819

【化学名称】N-Benzyl-2(S)-[2(S)-(2-hydroxyacetyl)pyrrolidin-1-ylcarbonyl]pyrrolidine-1-carboxamide
　　　　　　N-Benzylcarbamoyl-L-prolyl-L-prolyl-methanol

【CA登记号】162203-65-8

【分子式】C₁₉H₂₅N₃O₄

【分子量】359.4288

【开发单位】Japan Tobacco (Originator), Mitsubishi Pharma (Originator)

【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Prolyl Endopeptidase (prolyl oligopeptidase; POP) Inhibitors

合成路线1 合成路线2

合成路线1

1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with trimethylsulfonium iodide (II) and potassium tert-butoxide gives the epoxide (III), which is treated with benzyl alcohol and NaH to perform epoxide ring opening and simultaneous cyclization to yield the oxazolidinone (IV). The hydrolysis of (IV) with KOH affords compound (V), which is condensed with N-(benzylaminocarbonyl)-L-proline (VI) (prepared in situ with benzyl isocyanate (VII) and L-proline (VIII) in the presence of triethylamine) by means of diphenyl phosphoryl azide (DPPA) giving the dipeptide analogue (IX). The oxidation of (IX) with P2O5 in DMSO yields the benzylated JTP-4819 product (X), which is finally deprotected by hydrogenolysis with H2 over Pd/C.

参考文献中间体

【1】 Wroblewski, T.; Silvestre, J.S.; Castañer, J.; JTP-4819. Drugs Fut 1998, 23, 4, 384.
【2】 Fujiwara, T.; Iwamoto, Y.; Uchida, I.; Shinoda, M.; Abe, H.; Toide, K.; A novel prolyl endopeptidase inhibitor, JTP-4819, for the treatment of Alzheimer's disease: Review of preclinical pharmacology. CNS Drug Rev 1996, 2, 3, 343-62.

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)	16724	tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal	69610-41-9	C₁₀H₁₇NO₃	详情	详情
(II)	16725	trimethylsulfonium iodide	2181-42-2	C₃H₉IS	详情	详情
(III)	16726	tert-butyl (2S)-2-[(2R)oxiranyl]tetrahydro-1H-pyrrole-1-carboxylate		C₁₁H₁₉NO₃	详情	详情
(IV)	16727	(1R,7aS)-1-[(benzyloxy)methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one		C₁₄H₁₇NO₃	详情	详情
(V)	16728	(1R)-2-(benzyloxy)-1-[(2S)tetrahydro-1H-pyrrol-2-yl]-1-ethanol		C₁₃H₁₉NO₂	详情	详情
(VI)	16729	(2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₆N₂O₃	详情	详情
(VII)	16730	1-(Isocyanatomethyl)benzene; Benzyl Isocyanate	3173-56-6	C₈H₇NO	详情	详情
(VIII)	16731	L-proline	147-85-3	C₅H₉NO₂	详情	详情
(IX)	16732	(2S)-N-benzyl-2-([(2S)-2-[(1R)-2-(benzyloxy)-1-hydroxyethyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide		C₂₆H₃₃N₃O₄	详情	详情
(X)	16733	(2S)-N-benzyl-2-([(2S)-2-[2-(benzyloxy)acetyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide		C₂₆H₃₁N₃O₄	详情	详情

合成路线2

2) The reaction of tert-butoxycarbonyl-L-proline (XI) with diazomethane and triethylamine in ether gives the diazoketone (XII), which by treatment with acetic acid at 100 C yields the acetoxyketone (XIII). The deprotection of (XIII) with trifluoroacetic acid affords the unprotected alpha-hydroxyketone (XIV), which is condensed with N-(benzylaminecarbonyl)-L-proline (VI) by means of 1-hydroxybenzotriazole (HOBT) giving the acetylated dipeptide analogue (XV). Finally, this compound is deacetylated with K2CO3 in methanol/water.

参考文献中间体

【1】 Wroblewski, T.; Silvestre, J.S.; Castañer, J.; JTP-4819. Drugs Fut 1998, 23, 4, 384.
【2】 Kobayashi, K.; Akamatsu, M.; Yata, S.; Abe, H.; Toide, K.; Kogayu, M.; Uchida, I. (Japan Tobacco Inc.; Welfide Corporation); Cpd. with prolyl endopeptidase inhibitor activity and pharmaceutical use thereof. EP 0670309; JP 1995512967; US 5536737; WO 9412474 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	16729	(2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₆N₂O₃	详情	详情
(XI)	16734	(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₄	详情	详情
(XII)	16735	tert-butyl (2S)-2-(2-diazoacetyl)tetrahydro-1H-pyrrole-1-carboxylate	101130-03-4	C₁₁H₁₇N₃O₃	详情	详情
(XIII)	16736	tert-butyl (2S)-2-[2-(acetoxy)acetyl]tetrahydro-1H-pyrrole-1-carboxylate		C₁₃H₂₁NO₅	详情	详情
(XIV)	16737	2-oxo-2-[(2S)tetrahydro-1H-pyrrol-2-yl]ethyl acetate		C₈H₁₃NO₃	详情	详情
(XV)	16738	2-[(2S)-1-([(2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrol-2-yl]carbonyl)tetrahydro-1H-pyrrol-2-yl]-2-oxoethyl acetate		C₂₁H₂₇N₃O₅	详情	详情

Extended Information