4-aminocyclohexylamine; 1,4-cyclohexanediamine -Drug Synthesis Database

【结构式】

【分子编号】43407

【品名】4-aminocyclohexylamine; 1,4-cyclohexanediamine

【CA登记号】3114-70-3

【分子式】C₆H₁₄N₂

【分子量】114.19064

【元素组成】C 63.11% H 12.36% N 24.53%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(X)

D,L-Glutamic acid (I) was sequentially protected as the gamma-allyl ester (III), upon treatment with allyl alcohol (II) and chlorotrimethylsilane, followed by conversion to the trichloroethyl carbamate (V) by means of chloroformate (IV), and then reaction of (V) with benzyl bromide to afford the alpha-benzyl ester (VI). Deprotection of the trichloroethyl carbamate of (VI) by treatment with zinc dust and HOAc and subsequent condensation of the resulting amine with decanoyl chloride (VII) furnished amide (VIII). The allyl ester of (VIII) was then selectively cleaved by using tetrakistriphenylphosphine palladium(0) and morpholine to give carboxylic acid (IX). trans-1,4-Diaminocyclohexane (X) was protected as the mono tert-butyl carbamate (XI) and then coupled with acid (IX) in the presence of diethylphosphoryl cyanide to yield amide (XII). After acidic Boc cleavage of (XII), coupling of the resulting amine with 2,5-diphenyloxazole-4-carboxylic acid (XIII) by means of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) afforded (XIV). Finally, hydrolysis of the benzyl ester of (XIV) with LiOH provided the corresponding carboxylic acid.

参考文献中间体

合成目标

【1】 Ducruet, A.P.; Yokokawa, F.; Rice, R.L.; tamura, K.; Lazo, J.S.; Wipf, P.; Yokokama, S.; Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array. Bioorg Med Chem 2000, 8, 6, 1451.

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)	28752	DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid	617-65-2	C₅H₉NO₄	详情	详情
(II)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(III)	43406	5-(allyloxy)-5-oxonorvaline		C₈H₁₃NO₄	详情	详情
(IV)	13664	1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate	17341-93-4	C₃H₂Cl₄O₂	详情	详情
(V)	43399	5-(allyloxy)-5-oxo-N-[(2,2,2-trichloroethoxy)carbonyl]norvaline		C₁₁H₁₄Cl₃NO₆	详情	详情
(VI)	43400	5-allyl 1-benzyl 2-[[(2,2,2-trichloroethoxy)carbonyl]amino]pentanedioate		C₁₈H₂₀Cl₃NO₆	详情	详情
(VII)	28271	decanoyl chloride	112-13-0	C₁₀H₁₉ClO	详情	详情
(VIII)	43401	5-allyl 1-benzyl 2-(decanoylamino)pentanedioate		C₂₅H₃₇NO₅	详情	详情
(IX)	43402	5-(benzyloxy)-4-(decanoylamino)-5-oxopentanoic acid		C₂₂H₃₃NO₅	详情	详情
(X)	43407	4-aminocyclohexylamine; 1,4-cyclohexanediamine	3114-70-3	C₆H₁₄N₂	详情	详情
(XI)	43408	tert-butyl 4-aminocyclohexylcarbamate		C₁₁H₂₂N₂O₂	详情	详情
(XII)	43409	benzyl 5-([4-[(tert-butoxycarbonyl)amino]cyclohexyl]amino)-2-(decanoylamino)-5-oxopentanoate		C₃₃H₅₃N₃O₆	详情	详情
(XIII)	28277	2,5-diphenyl-1,3-oxazole-4-carboxylic acid		C₁₆H₁₁NO₃	详情	详情
(XIV)	43410	benzyl 2-(decanoylamino)-5-[(4-[[(2,5-diphenyl-1,3-oxazol-4-yl)carbonyl]amino]cyclohexyl)amino]-5-oxopentanoate		C₄₄H₅₄N₄O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

Reaction of phosphinylmethyl phosphonate (IV) with 1-iodo-4-nitrobenzene (V) in the presence of Pd(PPh3)4 affords the nitrophenyl phosphinoyl derivative (VI). Reduction of the nitro group of (VI) to the corresponding aniline (VII) is accomplished by treatment with SnCl2 in ethanol. Then, hydrolysis of the triethyl ester (VII) under acidic conditions furnishes phosphonic acid (VIII). Displacement of the 6-chloro group of purine (III) with the aminophenyl phosphonic acid (VIII) in hot DMSO gives rise to the 6-anilino purine (IX). Finally, displacement of the remaining halogen atom of (IX) with trans-1,4-diaminocyclohexane (X) leads to the title 2,6-diaminopurine compound.

参考文献中间体

合成目标

【1】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. US 2002068721 .
【2】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. WO 0144259 .
【3】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III (Ariad Pharmaceuticals Inc.); Novel purines. WO 0144260 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	61001	6-chloro-9-ethyl-2-fluoro-9H-purine		C₇H₆ClFN₄	详情	详情
(IV)	61002	diethyl [ethoxy(oxo)phosphoranyl]methylphosphonate		C₇H₁₈O₅P₂	详情	详情
(V)	21845	1-iodo-4-nitrobenzene	636-98-6	C₆H₄INO₂	详情	详情
(VI)	61003	diethyl [ethoxy(4-nitrophenyl)phosphoryl]methylphosphonate		C₁₃H₂₁NO₇P₂	详情	详情
(VII)	61004	diethyl [(4-aminophenyl)(ethoxy)phosphoryl]methylphosphonate		C₁₃H₂₃NO₅P₂	详情	详情
(VIII)	61005	[(4-aminophenyl)(hydroxy)phosphoryl]methylphosphonic acid		C₇H₁₁NO₅P₂	详情	详情
(IX)	61006	[{4-[(9-ethyl-2-fluoro-9H-purin-6-yl)amino]phenyl}(hydroxy)phosphoryl]methylphosphonic acid		C₁₄H₁₆FN₅O₅P₂	详情	详情
(X)	43407	4-aminocyclohexylamine; 1,4-cyclohexanediamine	3114-70-3	C₆H₁₄N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

1,4-Diaminocyclohexane (I) is converted into the mono-carbamate (II) employing di-tert-butyl dicarbonate in cold THF. Subsequent reduction of carbamate (II) by means of LiAlH4 leads to the N-methyl amine (III). After blocking the primary amino group of (III) as the corresponding benzaldimine (IV), treatment with di-tert-butyl dicarbonate gives rise to the mono-protected diamine (V). (1,2)

参考文献中间体

合成目标

【1】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Porter, J.; Rubin, L.E. (Curis, Inc.); Small organic molecule regulators of cell proliferation. US 6613798; US 6683108; WO 0174344 .
【2】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Porter, J.; Rubin, L.; Stibbard, J.H.A. (Curis, Inc.); Small organic molecule regulators of cell proliferation. US 2002198236; WO 0327234 .

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)	43407	4-aminocyclohexylamine; 1,4-cyclohexanediamine	3114-70-3	C₆H₁₄N₂	详情	详情
(II)	43408	tert-butyl 4-aminocyclohexylcarbamate		C₁₁H₂₂N₂O₂	详情	详情
(III)	63695	N~1~-methyl-1,4-cyclohexanediamine		C₇H₁₆N₂	详情	详情
(IV)	63696	N~1~-methyl-N~4~-(phenylmethylidene)-1,4-cyclohexanediamine		C₁₄H₂₀N₂	详情	详情
(V)	63697	1,1-dimethylethyl 4-aminocyclohexyl(methyl)carbamate		C₁₂H₂₄N₂O₂	详情	详情

Extended Information