tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate -Drug Synthesis Database

【结构式】

【分子编号】22345

【品名】tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate

【CA登记号】

【分子式】C₁₂H₂₂N₂O₄S

【分子量】290.38376

【元素组成】C 49.64% H 7.64% N 9.65% O 22.04% S 11.04%

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：(II)

The reaction of S-methylisothiourea (I) with Boc2O by means of NaHCO3 gives the N-Boc protected isothiourea (II), which is condensed with 1,4-butanediamine (III) in hot THF to yield the guanidine derivative (IV). The acylation of the amino group of (IV) with 3,4-dimethoxycinnamoyl chloride (V) with THF/DMF affords the corresponding amide (VI), which is deprotected with TFA to provide N-(4-guanidinobutyl)-3,4-dimethoxycinnamamide (VII). Finally, the guanidino group of (VII) is alkylated with 3-methyl-2-butenyl bromide (VIII) catalyzed by DMAP in THF to provide the target, caracasanamide.

参考文献中间体

合成目标

【1】 Delle Monache, G.; Delle Monache, F.; Botta, B.; Bonnevaux Castillo, S.; Espinal, R.; De Luca, C.; Carmignani, M. (Consiglio Nazionale delle Ricerche); Guanidine derivs. having hypotensive activity, compsn. containing them, and process for obtaining them. EP 0330629; JP 1990003661; US 5059624 .

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)	10272	[[Amino(imino)methyl]sulfanyl]methane	2986-19-8	C₂H₆N₂S	详情	详情
(II)	22345	tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate		C₁₂H₂₂N₂O₄S	详情	详情
(III)	42070	1,4-butanediamine; 4-aminobutylamine	110-60-1	C₄H₁₂N₂	详情	详情
(IV)	53109	tert-butyl (Z)-[(4-aminobutyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate	n/a	C₁₅H₃₀N₄O₄	详情	详情
(V)	33601	(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl chloride		C₁₁H₁₁ClO₃	详情	详情
(VI)	53110	tert-butyl (Z)-[(tert-butoxycarbonyl)amino][(4-{[(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl]amino}butyl)amino]methylidenecarbamate	n/a	C₂₆H₄₀N₄O₇	详情	详情
(VII)	53111	(E)-N-(4-{[amino(imino)methyl]amino}butyl)-3-(3,4-dimethoxyphenyl)-2-propenamide	n/a	C₁₆H₂₄N₄O₃	详情	详情
(VIII)	12989	4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene	870-63-3	C₅H₉Br	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Monoalkylation of 1,3-propanediamine (I) with 4-chlorobutanol (II) in refluxing n-BuOH afforded diaminoalcohol (III), which was protected as the bis-carbamate (IV) upon treatment with Boc2O. Subsequent reaction of (IV) with methanesulfonyl chloride and Et3N provided mesylate (V), and this was further treated with ethanolic ammonia to yield primary amine (VI). Condensation of amine (VI) with (methoxycarbonylmethyl) phenyl carbonate (VII) in refluxing toluene gave carbamate (VIII). Saponification of the methyl ester function of (VIII) then furnished carboxylic acid (IX). 1,6-Hexanediamine (X) was condensed with N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (XI) to produce the (6-aminohexyl)guanidine derivative (XII). This was then coupled with carboxylic acid (IX) using DCC and HOBt. Finally, the N-Boc groups were deprotected with trifluoroacetic acid in CH2Cl2.

参考文献中间体

合成目标

【1】 Lebreton, L.; Annat, J.; Derrepas, P.; Dutartre, P.; Renaut, P.; Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety. J Med Chem 1999, 42, 2, 277.

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)	19331	3-aminopropylamine; 1,3-propanediamine	109-76-2	C₃H₁₀N₂	详情	详情
(II)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(III)	22337	4-[(3-aminopropyl)amino]-1-butanol		C₇H₁₈N₂O	详情	详情
(IV)	22338	tert-butyl 3-[(tert-butoxycarbonyl)amino]propyl(4-hydroxybutyl)carbamate		C₁₇H₃₄N₂O₅	详情	详情
(V)	22339	4-((tert-butoxycarbonyl)[3-[(tert-butoxycarbonyl)amino]propyl]amino)butyl methanesulfonate		C₁₈H₃₆N₂O₇S	详情	详情
(VI)	22340	tert-butyl 4-aminobutyl[3-[(tert-butoxycarbonyl)amino]propyl]carbamate		C₁₇H₃₅N₃O₄	详情	详情
(VII)	22341	methyl 2-[(phenoxycarbonyl)oxy]acetate		C₁₀H₁₀O₅	详情	详情
(VIII)	22342	methyl 9-(tert-butoxycarbonyl)-2,2-dimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oate		C₂₁H₃₉N₃O₈	详情	详情
(IX)	22343	9-(tert-butoxycarbonyl)-2,2-dimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oic acid		C₂₀H₃₇N₃O₈	详情	详情
(X)	22344	1,6-hexanediamine; 6-aminohexylamine	124-09-4	C₆H₁₆N₂	详情	详情
(XI)	22345	tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate		C₁₂H₂₂N₂O₄S	详情	详情
(XII)	22346	tert-butyl (Z)-[(6-aminohexyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate		C₁₇H₃₄N₄O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

The ring opening of (-)-2-azabicyclo [2,2,1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA, yielding the carbamate (III). The cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) along with other isomers that are separated by column chromatography. Compound (V) is hydrogenated with H2 over PtO2 in methanol to provide amine (VI), which is acylated with Ac2O, giving the acetamide (VII). N-Boc deprotection of (VII) by means of HCl in ethyl ether yields the amine (VIII), which is condensed with protected isothiourea (IX) by means of HgCl2 to afford the guanidine derivative (X). The hydrolysis of (X) with NaOH provides the carboxylic acid (XI), which is finally deprotected with trifluoroacetic acid to yield the target cyclopentanecarboxylic acid derivative.

参考文献中间体

合成目标

【1】 Chand, P.; et al.; Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. J Med Chem 2001, 44, 25, 4379.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	33410	cis-2-azabicyclo[2.2.1]hept-5-en-3-one	C₆H₇NO	详情	详情
(II)	33412	methyl cis-4-amino-2-cyclopentene-1-carboxylate	C₇H₁₁NO₂	详情	详情
(III)	33413	methyl cis-4-[(tert-butoxycarbonyl)amino]-2-cyclopentene-1-carboxylate	C₁₂H₁₉NO₄	详情	详情
(IV)	33414	3-(nitromethyl)pentane	C₆H₁₃NO₂	详情	详情
(V)	33415	methyl (3aR,4R,6S,6aS)-4-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-6-carboxylate	C₁₈H₃₀N₂O₅	详情	详情
(VI)	45760	methyl (1S,2S,3S,4R)-3-[(1S)-1-amino-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate	C₁₈H₃₄N₂O₅	详情	详情
(VII)	45761	methyl (1S,2S,3S,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate	C₂₀H₃₆N₂O₆	详情	详情
(VIII)	45762	methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-amino-2-hydroxycyclopentanecarboxylate	C₁₅H₂₈N₂O₄	详情	详情
(IX)	22345	tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate	C₁₂H₂₂N₂O₄S	详情	详情
(X)	55003	methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetylamino)-2-ethylbutyl]-4-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-2-hydroxycyclopentanecarboxylate	C₂₆H₄₆N₄O₈	详情	详情
(XI)	55004	(1S,2S,3R,4R)-3-[(1S)-1-(acetylamino)-2-ethylbutyl]-4-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-2-hydroxycyclopentanecarboxylic acid	C₂₅H₄₄N₄O₈	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

1,3-Diaminopropane (I) is mono-protected with benzyl chloroformate, producing carbamate (II). Coupling of (II) with N,N'-bis-Boc-S-methylisothiourea (III) yields the Boc-protected guanidine (IV). The benzyloxycarbonyl group of (IV) is then removed by catalytic hydrogenolysis to furnish the noragmatine derivative (V)

参考文献中间体

合成目标

【1】 Szelke, M.; Evans, D.M.; Jones, D.M. (Ferring AB); Kininogen inhibitors. WO 9507291 .

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)	19331	3-aminopropylamine; 1,3-propanediamine	109-76-2	C₃H₁₀N₂	详情	详情
(II)	62059	benzyl 3-aminopropylcarbamate		C₁₁H₁₆N₂O₂	详情	详情
(III)	22345	tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate		C₁₂H₂₂N₂O₄S	详情	详情
(IV)	62060	benzyl 3-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)propylcarbamate		C₂₂H₃₄N₄O₆	详情	详情
(V)	26836	tert-butyl (Z)-[(3-aminopropyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate		C₁₄H₂₈N₄O₄	详情	详情

Extended Information