1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate -Drug Synthesis Database

【结构式】

【分子编号】32442

【品名】1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate

【CA登记号】

【分子式】C₂₂H₃₄I₂N₂O₆

【分子量】676.33078

【元素组成】C 39.07% H 5.07% I 37.53% N 4.14% O 14.19%

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：(XXX)

The reaction of 5-iodo-4-methyl-3-(tert-butydimethylsilyloxy)-4-pentenal (XXVI) with methyl iodide and CrCl2 in dioxane/THF gives the diiodohexenal (XXVII), which is desilylated with TBAF in THF yielding the secondary alcohol (XXVIII). The esterification of (XXVIII) with protected perhydropyridazinecarboxylic acid (XXIX) by means of EDC and DIEA in dichloromethane affords the carboxylic ester (XXX), which is deprotected with TFA in dichloromethane to give the unprotected ester (XXXI). The condensation of (XXXI) with carboxylic acid (XXXII) by means of 1-hydroxy-7-azabenzotriazole (HOAt) and EDC in dichloromethane yields the protected amide (XXXIII), which is deprotected with TFA affording (XXXIV) with a free amino group. The condensation of (XXXIV) with the acid (XXXV) (obtained by oxidation of carbinol (XXXVI) with tetrapropylammonium perruthenate (TPAP)) by means of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA in DMF provides the amide (XXXVII), which is cyclized by means of triphenylarsine and Pd dibenzylideneacetone complex yielding the cyclic intermediate (XXXVIII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXVI)	32438	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal	C₁₂H₂₃IO₂Si	详情	详情
(XXVII)	32439	tert-butyl([(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl ether	C₁₃H₂₄I₂OSi	详情	详情
(XXVIII)	32440	(1E,3S,5E)-1,6-diiodo-2-methyl-1,5-hexadien-3-ol	C₇H₁₀I₂O	详情	详情
(XXIX)	32441	(3S)-1,2-bis(tert-butoxycarbonyl)hexahydro-3-pyridazinecarboxylic acid	C₁₅H₂₆N₂O₆	详情	详情
(XXX)	32442	1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate	C₂₂H₃₄I₂N₂O₆	详情	详情
(XXXI)	32443	(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)hexahydro-3-pyridazinecarboxylate	C₁₂H₁₈I₂N₂O₂	详情	详情
(XXXII)	32444	(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propionic acid	C₁₉H₂₈N₂O₆	详情	详情
(XXXIII)	32445	(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate	C₃₁H₄₄I₂N₄O₇	详情	详情
(XXXIV)	32446	(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate	C₂₆H₃₆I₂N₄O₅	详情	详情
(XXXV)	32447	(3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid	C₂₄H₄₄O₄Sn	详情	详情
(XXXVI)	32448	[(3R,4S,5S,6S)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol	C₂₄H₄₆O₃Sn	详情	详情
(XXXVII)	32449	(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[([(3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]carbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate; (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[([(3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]carbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate	C₅₀H₇₈I₂N₄O₈Sn	详情	详情
(XXXVIII)	32450	(4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone; (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone	C₃₈H₅₁IN₄O₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XLVII)

The condensation of 3-hydroxybenzaldehyde (XXXIV) with phosphonate (XXXV) by means of DBU in dichloromethane gives the propenoic ester (XXXVI), which is enanthioselectively reduced catalyzed by (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate ((S,S)-DuP-Rh+OTf-) yielding the L-phenylalanine derivative (XXXVII). The deprotection of (XXXVII) by hydrogenation as usual affords the free amino acid (XXXVIII), which is condensed with Boc-L-valine (XXXIX) by means of EDC and HOAt to afford the dipeptide (XL). Hydrolysis of the ester group of (XXXIX) with LiOH in THF/water affords the N-protected amino acid (XLI), which is condensed with the perhydropyridazine (XLII) by means of EDC and HOAt to give the protected intermediate (XLIII). Finally, this compound is deprotected with TFA in dichloromethane to afford the desired intermediate the bis(iodovinyl) compound (XXXI). The intermediate perhydropyridazine (XLII) has been obtained as follows: The reaction of the iodoaldehyde (XLIV) with iodoform and CrCl2 in dioxane/THF gives the 1,6-diiodohexadiene (XLV), which, previous desilylation with TBAF, is condensed with the protected hexahydropyridazinecarboxylic acid (XLVI) by means of EDC, 4-Ppy and DIEA in dichloromethane to provide the protected diiodo ester (XLVII). Finally, this compound is deprotected with TFA in dichloromethane to yield the desired intermediate the perhydropyridazine (XLII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXI)	32446	(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate		C₂₆H₃₆I₂N₄O₅	详情	详情
(XXXIV)	28537	3-hydroxybenzaldehyde	100-83-4	C₇H₆O₂	详情	详情
(XXXV)	35887	methyl 2-[[(benzyloxy)carbonyl]amino]-2-(diethoxyphosphoryl)acetate		C₁₅H₂₂NO₇P	详情	详情
(XXXVI)	35888	methyl (E)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)-2-propenoate		C₁₈H₁₇NO₅	详情	详情
(XXXVII)	35889	methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)propanoate		C₁₈H₁₉NO₅	详情	详情
(XXXVIII)	35890	methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate		C₁₀H₁₃NO₃	详情	详情
(XXXIX)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(XL)	35891	methyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoate		C₂₀H₃₀N₂O₆	详情	详情
(XLI)	32444	(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propionic acid		C₁₉H₂₈N₂O₆	详情	详情
(XLII)	32443	(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)hexahydro-3-pyridazinecarboxylate		C₁₂H₁₈I₂N₂O₂	详情	详情
(XLIII)	32445	(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate		C₃₁H₄₄I₂N₄O₇	详情	详情
(XLIV)	32438	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal		C₁₂H₂₃IO₂Si	详情	详情
(XLV)	32439	tert-butyl([(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl ether		C₁₃H₂₄I₂OSi	详情	详情
(XLVI)	32441	(3S)-1,2-bis(tert-butoxycarbonyl)hexahydro-3-pyridazinecarboxylic acid		C₁₅H₂₆N₂O₆	详情	详情
(XLVII)	32442	1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate		C₂₂H₃₄I₂N₂O₆	详情	详情

Extended Information