(E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid -Drug Synthesis Database

【结构式】

【分子编号】68733

【品名】(E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid

【CA登记号】　

【分子式】C₉H₁₁NO₄

【分子量】197.19068

【元素组成】C 54.82% H 5.62% N 7.1% O 32.45%

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：(XXXVII)

The tetracyclic aldehyde (I) is prepared as follows. Heck coupling of 3-bromo-3-cyclohexen-1-one ethylene ketal (XIII) with methyl acrylate (XIV) in the presence of PdCl2(PPh3)2 and Et3N in DMF at 75 °C gives the dienoate ester (XV), which is hydrolyzed to the corresponding carboxylic acid (XVI) using NaOH in THF/MeOH. Subsequent DCC-mediated coupling of acid (XVI) with alcohol (XVII) in the presence of 4-pyrrolidinopyridine (4-Ppy) in CH2Cl2 affords the triene ester (XVIII). Intramolecular Diels–Alder reaction in triene (XVIII) by heating in xylene at 215 °C results in a tetracyclic intermediate, which undergoes epimerization at C9a by means of DBU in THF to provide the cis-lactone (XIX). The benzyl ester group of (XIX) is then removed by catalytic hydrogenolysis over Pd/C in EtOAc, and subsequent diastereoselective hydrogenation of the internal double bond over PtO2 in EtOAc affords the tetracyclic carboxylic acid (XX). Finally,chlorination of acid (XX) with SOCl2 in toluene at 180 °C followed by reduction of the resulting acid chloride with Bu3SnH in the presence of Pd(PPh3)4 in toluene yields the key aldehyde (I) .
Hydroxy ester (XVII) is obtained by protection of 2(R)-butynol (XXI) as the corresponding tetrahydropyranyl ether (XXII) with DHP in the presence of p-TsOH. Subsequent deprotonation of the terminal alkyne in compound (XXII) by means of BuLi and treatment with PhCH2OCOCl in THF at –78 °C followed by acidic THP group hydrolysis yields benzyl ester (XXIII), which is finally submitted to partial reduction of the triple bond by hydrogenation over Lindlar catalyst in THF .

参考文献中间体

合成目标

【2】 Chackalamannil, S., Asberom, T., Xia, Y., Doller, D., Clasby, M.C.,Czarniecki, M.F. Thrombin receptor antagonists. US 6063847.
【1】 Clasby, M.C., Chackalamannil, S., Czarniecki, M. et al. Metabolism-based identification of a potent thrombin receptor antagonist. J Med Chem 2007, 50(1): 129-38.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXII)	68728	(R,E)-4-hydroxy-N,N-diphenylpent-2-enamide;4(R)-hydroxy-N,Ndiphenyl-2-pentenamide		C₁₇H₁₇NO₂	详情	详情
(I)	68713	(1'R,3a'R,4a'R,8a'R,9a'S)-1'-methyl-3'- oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho [2,3-c]furan]-9'-carbaldehyde		C₁₆H₂₂O₅	详情	详情
(IX)	68708	(3S,3aS,4R,4aS,7S,8aS,9aS)-7-amino-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid		C₁₄H₂₁NO₄	详情	详情
(XIII)	68714	3-bromo-3-cyclohexen-1-one ethylene ketal；7-bromo-1,4-Dioxaspiro[4.5]dec-7-ene	81036-84-2	C₈H₁₁BrO₂	详情	详情
(XIV)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(XV)	68715	(E)-methyl 3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylate		C₁₂H₁₆O₄	详情	详情
(XVI)	68716	(E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid		C₁₁H₁₄O₄	详情	详情
(XVI)	68716	(E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid		C₁₁H₁₄O₄	详情	详情
(XVII)	68717	(R,E)-benzyl 4-hydroxypent-2-enoate		C₁₂H₁₄O₃	详情	详情
(XVIII)	68718	(R,Z)-benzyl 4-(((E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acryloyl)oxy)pent-2-enoate		C₂₃H₂₆O₆	详情	详情
(XIX)	68721	(1'R,3a'R,8a'R,9'S,9a'S)-benzyl 1'-methyl-3'-oxo-3',3a',5',7',8',8a',9',9a'-octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxylate		C₂₃H₂₈O₆	详情	详情
(XX)	68722	(1'R,3a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxylic acid		C₁₆H₂₂O₆	详情	详情
(XXI)	68719	2(R)-butynol;(R)-but-3-yn-2-ol	42969-65-3	C₄H₆O	详情	详情
(XXI)	68719	2(R)-butynol;(R)-but-3-yn-2-ol	42969-65-3	C₄H₆O	详情	详情
(XXII)	68720	2-((R)-but-3-yn-2-yloxy)tetrahydro-2H-pyran		C₉H₁₄O₂	详情	详情
(XXIII)	68723	(R)-benzyl 4-hydroxypent-2-ynoate		C₁₂H₁₂O₃	详情	详情
(XXIII)	68723	(R)-benzyl 4-hydroxypent-2-ynoate		C₁₂H₁₂O₃	详情	详情
(XXVIII)	68724	(R)-(but-3-yn-2-yloxy)trimethylsilane		C₇H₁₄OSi	详情	详情
(XXIX)	68725	1-(diphenylcarbamoyl)imidazole;N,N-diphenyl-1H-imidazole-1-carboxamide		C₁₆H₁₃N₃O	详情	详情
(XXX)	68726	(R)-4-hydroxy-N,N-diphenylpent-2-ynamide;4(R)-hydroxy-N,N-diphenyl-2-pentynamide;4-hydroxy-N,N-diphenyl-(4R)-2-Pentynamide	899809-61-1	C₁₇H₁₅NO₂	详情	详情
(XXXI)	68727	4-hydroxy-N,N-diphenyl-2-pentynamide		C₁₇H₁₅NO₂	详情	详情
(XXXIII)	68729	(E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylate		C₂₈H₂₉NO₅	详情	详情
(XXXIV)	68730	(1'R,3a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxo-N,N-diphenyl-3',3a',5',7',8',8a',9',9a'-octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxamide		C₂₈H₂₉NO₅	详情	详情
(XXXV)	68731	(1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxo-N,N-diphenyldecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxamide		C₂₈H₃₁NO₅	详情	详情
(XXXVI)	68732	(3S,3aS,4R,4aS,8aS,9aS)-3-methyl-1,7-dioxododecahydronaphtho[2,3-c]furan-4-carboxylic acid		C₁₄H₁₈O₅	详情	详情
(XXXVII)	68733	(E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid		C₉H₁₁NO₄	详情	详情
(XXXVIII)	68735	(4R)-benzyl 4-(((E)-3-(5-nitrocyclohex-1-en-1-yl)acryloyl)oxy)pent-2-ynoate		C₂₁H₂₁NO₆	详情	详情
(XXXIX)	68734	(4R)-benzyl 4-(((E)-3-(5-nitrocyclohex-1-en-1-yl)acryloyl)oxy)pent-2-enoate		C₂₁H₂₃NO₆	详情	详情
(XL)	68736	(3S,3aS,4R,4aS,7R,9aS)-benzyl 3-methyl-7-nitro-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate		C₂₁H₂₃NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXXVII)

Conjugate addition of acrolein (LVIII) to nitromethane in the presence of KOH in MeOH followed by treatment with Na2S2O5 in H2O gives the nitrodisulfonate (LIX), which is hydrolyzed with glyoxylic acid by means of NaHCO3 to yield 4-nitroheptanedial (LX). Compound (LX) is cyclized in the presence of pyrrolidine and PhCOOH in CH2Cl2, providing 5-nitro-1-cyclohexenecarbaldehyde (LXI). Wittig reaction of aldehyde (LXI) with (methoxycarbonylmethylene)triphenylphosphorane (LXII) leads to conjugated ester (LXIII), which is finally saponified with NaOH .
Acid (XXXVII) can be alternatively prepared by Knoevenagel condensation of aldehyde (LXI) with malonic acid (LXIV) .
Hydrolysis of ethylene ketal (XVI) with aqueous p-toluenesulfonic acid gives ketone (LXV), which, without isolation, is converted to oxime (LXVI) by addition of hydroxylamine hydrochloride. Subsequent oxidation of oxime (LXVI) using sodium molybdate and H2O2 leads to compound (XXXVII) .

参考文献中间体

合成目标

【1】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.
【2】 Thiruvengadam, T.K., Wang, T., Chiu, J.S., Liao, J. (Schering Corp.). Synthesis of 3-(5-nitrocyclohex-1-enyl)acrylic acid and esters thereof. EP 2035364, JP 2009542675, US 2008009651, WO 2008005344.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	68716	(E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid		C₁₁H₁₄O₄	详情	详情
(XXXVII)	68733	(E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid		C₉H₁₁NO₄	详情	详情
(LVIII)	17668	acrylaldehyde; Acrolein	107-02-8	C₃H₄O	详情	详情
(LIX)	68754	sodium 1,7-dihydroxy-4-nitroheptane-1,7-disulfonate		C₇H₁₃NNa₂O₁₀S₂	详情	详情
(LX)	68755	4-nitroheptanedial		C₇H₁₁NO₄	详情	详情
(LXI)	68756	5-nitro-1-cyclohexenecarbaldehyde		C₇H₉NO₃	详情	详情
(LXII)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(LXIII)	68757	(E)-methyl 3-(5-nitrocyclohex-1-en-1-yl)acrylate		C₁₀H₁₃NO₄	详情	详情
(LXIV)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(LXV)	68758	(E)-3-(5-oxocyclohex-1-en-1-yl)acrylic acid		C₉H₁₀O₃	详情	详情
(LXVI)	68759	(E)-3-((E)-5-(hydroxyimino)cyclohex-1-en-1-yl)acrylic acid		C₉H₁₁NO₃	详情	详情

Extended Information