2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid -Drug Synthesis Database

【结构式】

【分子编号】13856

【品名】2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid

【CA登记号】77-92-9

【分子式】C₆H₈O₇

【分子量】192.12532

【元素组成】C 37.51% H 4.2% O 58.29%

与该中间体有关的原料药合成路线共 4 条

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

该中间体在本合成路线中的序号：(IV)

By condensation of 1,5-diphenyl-1-pentanol (I) with 3-(dimethylamino)propyl chloride (II) by means of NaH in refluxing toluene, followed by a treatment with citric acid.

参考文献中间体

合成目标

【1】 Ono, K.; Kawakami, H.; Katsube, J. (Sumitomo Pharmaceuticals Co., Ltd.); Diphenylalkanoether and diphenylalkanone oximeether derivatives. EP 0017217; US 4388469; US 4426394; US 4482573; US 4620036 .
【2】 Castaner, J.; Prous, J.; SM-3163. Drugs Fut 1986, 11, 12, 1046.

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)	24580	1,5-diphenyl-1-pentanol		C₁₇H₂₀O	详情	详情
(II)	24581	3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine	5407-04-5	C₅H₁₂ClN	详情	详情
(III)	24582	3-[(1,5-diphenylpentyl)oxy]-N,N-dimethyl-1-propanamine		C₂₂H₃₁NO	详情	详情
(IV)	13856	2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid	77-92-9	C₆H₈O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The reaction of 2-furan-methanol (I) with dimethylamine and formaldehyde gives 5-(dimethylaminomethyl)furan-2-methanol (II), which is condensed with 2-sulfanylethylamine (III) yielding 2-[5-(dimethylaminomethyl)furan-2-ylsulfanyl]ethylamine (IV). The condensation of (IV) with 1-(methylamino)-1-(methylsulfanyl)-2-nitroethylene (V), obtained from 1,1,-bis(methylsulfanyl)-2-nitroethylene (VI) and methylamine, in hot acetone, or by heating at 100-120 C affords N-[2-[5-(dimethylaminomethyl)furan-2-ylmethylsulfanyl]ethyl]- N'-methyl-2-nitroethylene-1,1-diamine (VII) , which is finally complexed with bismuth (+3) citrate (VIII), obtained by reaction of NO3BiO with citric acid (IX) in hot water.

参考文献中间体

合成目标

【1】 Castaner, J.; Rabasseda, X.; Mealy, N.; Ranitidine Bismuth Citrate. Drugs Fut 1995, 20, 5, 480.
【2】 Clitherow, J.W. (Glaxo Wellcome plc); Ranitidine derivs. BE 1003254; CH 679582; GB 2220937; JP 1990117684; US 5008256 .
【3】 Bradshaw, J.; Price, B.J.; Clitherow, J.W.; Aminoalkyl furan derivs. GB 1565966 .

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)	13848	2-Furylmethanol; Furfuryl Alcohol	98-00-0	C₅H₆O₂	详情	详情
(II)	13849	[5-[(dimethylamino)methyl]-2-furyl]methanol		C₈H₁₃NO₂	详情	详情
(III)	13186	2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine	60-23-1	C₂H₇NS	详情	详情
(IV)	13851	2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine		C₁₀H₁₈N₂OS	详情	详情
(V)	13852	N-Methyl-N-[(E)-1-(methylsulfanyl)-2-nitroethenyl]amine; (E)-N-Methyl-1-(methylsulfanyl)-2-nitro-1-ethenamine; (E)-1-Methylthio-1-methylamino-2-nitroethylene	61832-41-5	C₄H₈N₂O₂S	详情	详情
(VI)	13853	Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene	13623-94-4	C₄H₇NO₂S₂	详情	详情
(VII)	13854	N-[2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]-N-[(E)-1-(methylamino)-2-nitroethenyl]amine; (E)-N(1)-[2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]-N(1)-methyl-2-nitro-1,1-ethenediamine; Ranitidine	66357-35-5	C₁₃H₂₂N₄O₃S	详情	详情
(VIII)	13855	bismuth(3+) 2-hydroxy-1,2,3-propanetricarboxylate; Bismuth Citrate	813-93-4	C₆H₅BiO₇	详情	详情
(IX)	13856	2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid	77-92-9	C₆H₈O₇	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The peroxidation of 1,4-diphenyl-1-cyclopentadiene (I) with O2, white light and activated by tetraphenylporphyrin in dichloromethane gives the peroxide (II), which is condensed with cyclohexane-1,4-dione (III) by means of trimethylsilyl trifluoromethanesulfonate in dichloromethane, yielding the adduct (IV). The reductocondensation of (IV) with N-(7-chloroquinolin-4-yl)ethylenediamine (V) by means of NaBH(OAc)3 in dichloromethane affords the tricyclic trioxane (VI), which is finally treated with citric acid in acetone to provide the target citrate. The intermediate N-(7-chloroquinolin-4-yl)ethylenediamine (V) has been obtained by reaction of 4,7-dichloroquinoline (VIII) with ethylenediamine by means of NaOH at 85 C.

参考文献中间体

合成目标

【1】 Dechy-Cabaret, O.; et al.; Preparation of antimalarial activities of "trioxaquines", new modular molecules with a trioxane skeleton linked to a 4-aminoquinoline. ChemBioChem 2000, 1, 4, 281.
【2】 Robert, A.; Dechy Cabaret, O.; Meunier, B.; Benoit Vical, F. (CNRS (Centre National de la Recherche Scientifique)); Dual molecules containing a peroxide deriv., synthesis and therapeutic applications thereof. FR 2807433; WO 0177105 .

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)	51999	1-(4-phenyl-1,3-cyclopentadien-1-yl)benzene		C₁₇H₁₄	详情	详情
(II)	52000	1,4-diphenyl-2,3-dioxabicyclo[2.2.1]hept-5-ene		C₁₇H₁₄O₂	详情	详情
(III)	52001	1,4-Cyclohexanedione; Tetrahydro-p-benzoquinone	637-88-7	C₆H₈O₂	详情	详情
(IV)	52002			C₂₃H₂₂O₄	详情	详情
(V)	52003	N(1)-(6-chloro-1-naphthyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(6-chloro-1-naphthyl)amine		C₁₂H₁₃ClN₂	详情	详情
(VI)	52004			C₃₅H₃₅ClN₂O₃	详情	详情
(VII)	13856	2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid	77-92-9	C₆H₈O₇	详情	详情
(VIII)	52005	1,6-dichloronaphthalene		C₁₀H₆Cl₂	详情	详情
(IX)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Condensation of 2,5-dichlorobenzoyl chloride (I) with glycine (II) in the presence of NaOH in H2O/THF gives 2-(2,5-dichlorobenzoylamino) acetic acid (III), which then couples with the 1,3,2-benzodioxaborolyl butanamine derivative (IV) by means of TBTU and DIEA in DMF to yield peptide (V). O-Deprotection of 1,3,2-benzodioxaborolane (V) by means of HCl and 2-methylisopropyl boronic acid in methanol/hexane affords boroxin derivative (VI), which is finally esterified with citric acid (VII) in THF or MIBK or acetonitrile or 2-Me-THF or acetone or EtOAc .

参考文献中间体

合成目标

【1】 Elliott, E.L., Ferdous, A.J., Kaufman, M.J. et al. (Millennium Pharmaceuticals, Inc.). Boronate ester compounds and pharmaceutical compositions thereof. CN 102066386, EP 2318419, JP 2011524902, US 2009325903, WO 2009154737.

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)	68548	2,5-dichlorobenzoyl chloride;2,5-dichloro-benzoyl chlorid	2905-61-5	C₇H₃Cl₃O	详情	详情
(II)	20436	glycine	56-40-6	C₂H₅NO₂	详情	详情
(III)	68549	2-(2,5-dichlorobenzoylamino)acetic acid		C₉H₇Cl₂NO₃	详情	详情
(IV)	68550	(S)-3-methyl-1-((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butan-1-amine 2,2,2-trifluoroacetate		C₁₇H₂₈BNO₄.C₂HF₃O₂	详情	详情
(V)	68551	2,5-dichloro-N-(2-(((S)-3-methyl-1-((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-2-oxoethyl)benzamide		C₂₄H₃₃BCl₂N₂O₄	详情	详情
(VII)	13856	2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid	77-92-9	C₆H₈O₇	详情	详情

Extended Information