JMV-1640, -Drug Synthesis Database

【结构式】

【药物名称】JMV-1640

【化学名称】3(S)-[1'-(L-Lysyl-L-arginyl)-3-(2-phenylethyl)-5-oxospiro[imidazolidin-4,4'-piperidin]-1-yl]acetyl-L-serylamino]-4-oxo-3,4-dihydro-2H-1,5-benzothiazepine-5-acetic acid

【CA登记号】

【分子式】C₄₃H₆₂N₁₂O₉S

【分子量】923.11259

【开发单位】Fournier (Originator), INSERM (Originator), Université Montpellier I (Originator), Université Montpellier II (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Bradykinin B1 Antagonists

合成路线1 合成路线2

合成路线1

Synthesis of intermediate (XIV): Protection of 4-piperidone (I) with (Boc)2O in presence of DMAP and Et3N yields (II), which is converted into hydantoin (III) by means of NaCN in presence of (NH4)2CO3. Hydantoin (III) is then fully protected to provide (IV) by treatment with (Boc)2O and DMAP in THF. Alternatively (IV) can be obtained by treatment of 4-piperidone (I) with KCN in presence of (NH4)2CO3 to yield hydantoin (V), which is then protected with (Boc)2O and DMAP in DME. Hydrolysis of (IV) with NaOH affords aminoacid (VI) whose free amine is protected to provide carboxylic acid (VII). Treatment of (VII) with isobutyl chloroformate (IBCF) in DME in presence of NMM, followed by aqueous ammonia, yields amide (VIII), which is converted to (IX) by hydrogenation with H2 over Pd/C. Reductive amination of (IX) with aldehyde (X) affords amino amide (XI), which is treated with triethyl orthoformate to provide spirocycle (XII). Reduction of (XII) with NaBH4 in EtOH gives (XIII), which is alkylated with ethyl bromoacetate (A) followed by hydrolysis with NaOH to yield intermediate (XIV).

参考文献中间体

【1】 Wysong, C.L.; et al.; 4-Aminopiperidine-4-carboxamylic acid: A cyclic alpha,alpha-disubstituted amino acid for preparation of water-soluble highly helical peptides. J Org Chem 1996, 61, 22, 7650-51.
【2】 Amblard, M.; Subra, G.; Bedos, P.; et al.; A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist. J Med Chem 2000, 43, 12, 2387.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(I)	18178	4,4-piperidinediol	73390-11-1	C₅H₁₁NO₂	详情	详情
(II)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(III)	41678	tert-butyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate		C₁₂H₁₉N₃O₄	详情	详情
(IV)	41679	tri(tert-butyl) 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-1,3,8-tricarboxylate		C₂₂H₃₅N₃O₈	详情	详情
(V)	41680	1,3,8-triazaspiro[4.5]decane-2,4-dione	13625-39-3	C₇H₁₁N₃O₂	详情	详情
(VI)	41681	4-amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid	183673-71-4	C₁₁H₂₀N₂O₄	详情	详情
(VII)	41682	1-(tert-butoxycarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-piperidinecarboxylic acid		C₂₆H₃₀N₂O₆	详情	详情
(VIII)	41683	tert-butyl 4-(aminocarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1-piperidinecarboxylate		C₂₆H₃₁N₃O₅	详情	详情
(IX)	41684	tert-butyl 4-amino-4-(aminocarbonyl)-1-piperidinecarboxylate		C₁₁H₂₁N₃O₃	详情	详情
(X)	18456	2-phenylacetaldehyde	122-78-1	C₈H₈O	详情	详情
(XI)	41685	tert-butyl 4-(aminocarbonyl)-4-(phenethylamino)-1-piperidinecarboxylate		C₁₉H₂₉N₃O₃	详情	详情
(XII)	41686	tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-2-ene-8-carboxylate		C₂₀H₂₇N₃O₃	详情	详情
(XIII)	41687	tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate		C₂₀H₂₉N₃O₃	详情	详情
(XIV)	41688	2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid		C₂₂H₃₁N₃O₅	详情	详情

合成路线2

Synthesis of EN 290154: Cleavage of both the Fmoc protecting group and ethyl ester of (XV) by means of HBr in HOAc followed by Boc protection affords (XVI) which is then anchored to a chloromethylated resin to yield (XVII). Deprotection of dihydro-benzothiazepinone (XVII) with TFA in presence of ethanedithiol, followed by coupling with Boc-Ser-OH by means of BOP/DIEA in CH2Cl2, yields derivative (XVIII). Deprotection of (XVIIII) followed by coupling with intermediate (XIV) in the same conditions described for (XVII) affords derivative (XIX). Next steps include sequencial Boc removal and coupling with Boc-Arg(Tos)-OH and then Boc-Lys(Fmoc)-OH. Finally the product is cleaved from the resin by means of HF/anisole.

参考文献中间体

【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185.
【2】 Amblard, M.; Subra, G.; Bedos, P.; et al.; A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist. J Med Chem 2000, 43, 12, 2387.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVI),(XVII)	41690	2-[(3S)-3-[(tert-butoxycarbonyl)amino]-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid	C₁₇H₂₄N₂O₄S	详情	详情
(XIV)	41688	2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid	C₂₂H₃₁N₃O₅	详情	详情
(XV)	41689	ethyl 2-[(3S)-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate	C₂₉H₃₀N₂O₄S	详情	详情
(XVIII)	41691	2-[(3S)-3-([2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]amino)-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid	C₂₀H₂₉N₃O₆S	详情	详情
(XIX)	41692	2-[(3S)-3-[[2-([2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetyl]amino)-3-hydroxypropanoyl]amino]-3-methyl-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid	C₃₇H₅₀N₆O₈S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)