JMV-1645, -Drug Synthesis Database

【结构式】

【药物名称】JMV-1645

【化学名称】3(S)-[L-Lysyl-L-arginyl-L-prolyl-L-(trans-4-hydroxy)prolyl-glycyl-L-[alpha-(2-indanyl)]glycyl-L-serylamino]-4-oxo-3,4-dihydro-2H-1,5-benzothiazepine-5-acetic acid

【CA登记号】

【分子式】C₄₉H₆₉N₁₃O₁₂S

【分子量】1064.24018

【开发单位】CNRS (Originator), Fournier (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3 合成路线4

合成路线1

o-Fluoronitrobenzene (I) is converted into (III) by an aromatic nucleophilic substitution with N-Ac-Cysteine (II) in EtOH in the presence of NaHCO3. Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and in the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (Scheme 28946801a).

参考文献中间体

【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521.

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)	13463	o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene	1493-27-2	C₆H₄FNO₂	详情	详情
(II)	39365	(2S)-2-(acetamido)-3-sulfanylpropionic acid	616-91-1	C₅H₉NO₃S	详情	详情
(III)	43244	(2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid		C₁₁H₁₂N₂O₅S	详情	详情
(IV)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(V)	43245	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid		C₁₇H₁₆N₂O₆S	详情	详情
(VI)	43246	(2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid		C₁₇H₁₈N₂O₄S	详情	详情
(VII)	43247	benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate		C₁₇H₁₆N₂O₃S	详情	详情
(VIII)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(IX)	43248	ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate		C₂₁H₂₂N₂O₅S	详情	详情

合成路线2

Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in HOAc, followed by the introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH(XVI), Boc-Hyp-OH(XVIII) and Boc-Pro-OH(XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28946801b).

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.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX),(X)	43248	ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate		C₂₁H₂₂N₂O₅S	详情	详情
(XI)	43249	2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid		C₁₆H₂₀N₂O₅S	详情	详情
(XII)	28112	(2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid		C₁₅H₂₁NO₅	详情	详情
(XIII)	42350	ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate		C₉H₁₇NO₃	详情	详情
(XIV)	43251	(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoic acid		C₁₆H₂₁NO₄	详情	详情
(XV)	43252	2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid		C₃₇H₄₂N₄O₈S	详情	详情
(XVI)	18066	N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid	4530-20-5	C₇H₁₃NO₄	详情	详情
(XVII)	43253	2-[(3S)-3-[[(2R,5R)-2-[(benzyloxy)methyl]-5-(2,3-dihydro-1H-inden-2-yl)-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid		C₃₉H₄₅N₅O₉S	详情	详情
(XVIII)	19043	(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₅	详情	详情
(XIX)	43254	2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl]amino)acetyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic aci		C₄₄H₅₂N₆O₁₁S	详情	详情
(XX)	19061	(2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline		C₁₀H₁₇NO₄	详情	详情
(XXI)	43255	2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben		C₄₉H₅₉N₇O₁₂S	详情	详情

合成路线3

The peptidic chain is elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Arg(Tos)-OH (XXII), Boc-Lys(COOCH2Ph)-OH (XXIV)) with BOP/DIEA, providing derivative (XXIV). (Scheme 28946801c).

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.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXI)	43255	2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben	C₄₉H₅₉N₇O₁₂S	详情	详情
(XXII)	43256	(2S)-2-[(tert-butoxycarbonyl)amino]-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoic acid	C₁₈H₂₈N₄O₇S	详情	详情
(XXIII)	43257	2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-[(tert-butoxycarbonyl)amino]-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-	C₆₂H₇₇N₁₁O₁₆S₂	详情	详情
(XXIV)	23159	(2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid	C₁₉H₂₈N₂O₆	详情	详情
(XXV)	43258	2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-([(2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoyl]amino)-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbon	C₇₆H₉₅N₁₃O₁₉S₂	详情	详情

合成路线4

Derivative (XXIV) is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole. (Schemes 28946801d).

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.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXV)	43258	2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-([(2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoyl]amino)-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbon		C₇₆H₉₅N₁₃O₁₉S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)