2-(5-isoquinolinyloxy)acetic acid -Drug Synthesis Database

【结构式】

【分子编号】15840

【品名】2-(5-isoquinolinyloxy)acetic acid

【CA登记号】

【分子式】C₁₁H₉NO₃

【分子量】203.1974

【元素组成】C 65.02% H 4.46% N 6.89% O 23.62%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

1) The reaction of 3-(tert-butoxycarbonyl)thiazolidine-4(R)-carboxylic acid (I) with tert-butylamine by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding protected amide (II), which is deprotected with HCl or methanesulfonic acid to the free amide (III). The condensation of (III) with (2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyric acid (IV) by means of 1-hydroxybenzotriazole (HOBT) and DCC in DMF affords the dipeptide (V), which by deprotection with HCl in dioxane and condensation with 2(R)-(tert-butoxycarbonylamino)-3-(methylsulfanyl)propionic acid (VI) by means of HBOT and DCC as before yields the tripeptide (VII). Finally, this compound is deprotected with HCl as before and condensed with 2-(5-isoquinolinyloxy)acetic acid (VIII) by means of HBOT and DCC or HBOT and 5-norbornene-2,3-dicarboxyimide (NDPP) in DMF.

参考文献中间体

合成目标

【1】 Ireland, C.D.; Castaner, J.; KNI-272. Drugs Fut 1996, 21, 10, 1022.
【2】 Kiso, Y.; Design and synthesis of HIV protease inhibitors containing allophenylorstatine as a transition-state mimic. Adv Exp Med Biol 1995, 362(Aspartic Proteinases), Aspartic Proteinases, 413-23.
【3】 Maeda, S.; Moriwaki, H. (Hamari Chemicals Ltd.; Japan Energy Corp.); Manufacturing method for peptide derivs. and their salts. JP 1994220031 .
【4】 Mimoto, T.; Kisanuki, S.; Takahasihi, O.; Kiso, Y. (Japan Energy Corp.); Process for producing peptide derivs. and salts thereof. EP 0574135 .

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)	15833	(4R)-3-(tert-butoxycarbonyl)-1,3-thiazolane-4-carboxylic acid; N-t-BOC-4-thio-L-proline	51077-16-8	C₉H₁₅NO₄S	详情	详情
(II)	15834	tert-butyl (4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolane-3-carboxylate		C₁₃H₂₄N₂O₃S	详情	详情
(III)	15835	(4R)-N-(tert-butyl)-1,3-thiazolane-4-carboxamide		C₈H₁₆N₂OS	详情	详情
(IV)	15836	N-t-BOC-(2R,3R)-3-Amino-2-hydroxy-4-phenylbutyric acid; (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyric acid	116661-86-0	C₁₅H₂₁NO₅	详情	详情
(V)	15837	tert-Butyl N-((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolan-3-yl]-2-hydroxy-3-oxopropyl)carbamate		C₂₃H₃₅N₃O₅S	详情	详情
(VI)	15838	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(methylsulfanyl)propionic acid		C₉H₁₇NO₄S	详情	详情
(VII)	15839	tert-butyl (1R)-2-[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]-1-[(methylsulfanyl)methyl]-2-oxoethylcarbamate		C₂₇H₄₂N₄O₆S₂	详情	详情
(VIII)	15840	2-(5-isoquinolinyloxy)acetic acid		C₁₁H₉NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

2) The intermediate (V) of the preceding synthesis is submitted to a deprotection - protection sequence [hydrolysis with HCl in dioxane and protection with benzyl succinimidyl carbonate (PhCH2-OSu)] giving the benzyloxycarbonyl protected compound (IX), which is condensed with (VI) by means of DCC and dimethylaminopyridine (DMAP) to yield (X) [the ester isomer of (VII)]. The deprotection of (X) with HCl and condensation with (VIII) by means of HBOT and DCC as before affords (XI) [the benzyloxycarbonyl protected prodrug of KNI-272], which is deprotected with trifluoroacetic acid (TFA)/anisole and HCl affording the ester prodrug (XII). Finally, this compound is converted into KNI-272 by incubation at 37 C in a phosphate buffered saline at pH 7.4.

参考文献中间体

合成目标

【1】 Kimura, T.; Ohtake, J.; Nakata, S.; Enomoto, H.; Moriwaki, H.; Akaji, K.; Kiso, Y.; Synthesis and prodrugs of HIV protease inhibitors. Peptide Chem 1994, 157-60.
【2】 Ireland, C.D.; Castaner, J.; KNI-272. Drugs Fut 1996, 21, 10, 1022.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	15837	tert-Butyl N-((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolan-3-yl]-2-hydroxy-3-oxopropyl)carbamate	C₂₃H₃₅N₃O₅S	详情	详情
(VI)	15838	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(methylsulfanyl)propionic acid	C₉H₁₇NO₄S	详情	详情
(VIII)	15840	2-(5-isoquinolinyloxy)acetic acid	C₁₁H₉NO₃	详情	详情
(IX)	15841	benzyl N-((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolan-3-yl]-2-hydroxy-3-oxopropyl)carbamate	C₂₆H₃₃N₃O₅S	详情	详情
(X)	15842	(1S,2S)-2-[[(benzyloxy)carbonyl]amino]-1-([(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]carbonyl)-3-phenylpropyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(methylsulfanyl)propanoate	C₃₅H₄₈N₄O₈S₂	详情	详情
(XI)	15843	(1S,2S)-2-[[(benzyloxy)carbonyl]amino]-1-([(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]carbonyl)-3-phenylpropyl (2R)-2-[[2-(5-isoquinolinyloxy)acetyl]amino]-3-(methylsulfanyl)propanoate	C₄₁H₄₇N₅O₈S₂	详情	详情
(XII)	15844	(1S,2S)-2-amino-1-([(4R)-4-[(tert-butylamino)carbonyl]-1,3-thiazolidin-3-yl]carbonyl)-3-phenylpropyl (2R)-2-[[2-(5-isoquinolinyloxy)acetyl]amino]-3-(methylsulfanyl)propanoate	C₃₃H₄₁N₅O₆S₂	详情	详情

Extended Information