tert-butyl 2,2,2-trichloroethanimidoate -Drug Synthesis Database

【结构式】

【分子编号】61667

【品名】tert-butyl 2,2,2-trichloroethanimidoate

【CA登记号】

【分子式】C₆H₁₀Cl₃NO

【分子量】218.50964

【元素组成】C 32.98% H 4.61% Cl 48.67% N 6.41% O 7.32%

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：

N-Boc-L-Phenylalanine (I) is converted into the tert-butyl ester (II) upon treatment with tert-butyl trichloroacetimidate and boron trifluoride. Then, selective removal of the N-Boc group of (II) with HCl in EtOAc provides L-phenylalanine ester (III). Coupling of (III) with N-Cbz-2-methylproline (IV) furnishes dipeptide (V). After hydrogenolysis of the N-Cbz group of (V), the resultant amine (VI) is acylated by means of 3,5-dichlorobenzenesulfonyl chloride (VII), yielding sulfonamide (VIII). The tert-butyl ester group of (VIII) is finally cleaved by treatment with trifluoroacetic acid in CH2Cl2

参考文献中间体

合成目标

【1】 Hagmann, W.K.; Durette, P.L.; Mumford, R.A.; Mills, S.G.; Kevin, N.J.; Schmidt, J.A.; MacCoss, M.; Van Riper, G.M. (Merck & Co., Inc.); Heterocyclic amide cpds. as cell adhesion inhibitors. EP 1001764; WO 9853814 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	61667	tert-butyl 2,2,2-trichloroethanimidoate	C₆H₁₀Cl₃NO	详情	详情
(I)	22184	(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid	C₁₄H₁₉NO₄	详情	详情
(II)	60836	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate	C₁₈H₂₇NO₄	详情	详情
(III)	60837	tert-butyl (2S)-2-amino-3-phenylpropanoate	C₁₃H₁₉NO₂	详情	详情
(IV)	60838	(2S)-1-[(benzyloxy)carbonyl]-2-methyl-2-pyrrolidinecarboxylic acid	C₁₄H₁₇NO₄	详情	详情
(V)	60839	benzyl (2S)-2-({[(1S)-1-benzyl-2-(tert-butoxy)-2-oxoethyl]amino}carbonyl)-2-methyl-1-pyrrolidinecarboxylate	C₂₇H₃₄N₂O₅	详情	详情
(VI)	60840	tert-butyl (2S)-2-({[(2S)-2-methylpyrrolidinyl]carbonyl}amino)-3-phenylpropanoate	C₁₉H₂₈N₂O₃	详情	详情
(VII)	59023	3,5-dichlorobenzenesulfonyl chloride	C₆H₃Cl₃O₂S	详情	详情
(VIII)	60841	tert-butyl (2S)-2-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methylpyrrolidinyl}carbonyl)amino]-3-phenylpropanoate	C₂₅H₃₀Cl₂N₂O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(A)

A synthesis leading to the pure anti isomer has also been reported. Cycloaddition of dichloroketene, generated in situ from trichloroacetyl chloride and Zn-Cu couple, to allyl benzyl ether (I) produces the dichloro cyclobutanone (II). Subsequent reduction of the dichloro compound (II) with Zn dust in AcOH gives 3-(benzyloxymethyl)cyclobutanone (III). Reaction of cyclobutanone (III) with KCN and (NH4)2CO3 furnishes a mixture of the isomeric hydantoins (IV) and (V), separable by column chromatography. The minor anti isomer (V) is subsequently hydrolyzed under alkaline conditions to provide aminoacid (VI). After protection of (VI) as the N-Boc derivative (VII), treatment with t-butyl trichloroacetimidate gives the tert-butyl ester (VIII). Removal of the O-benzyl group of (VIII) by catalytic hydrogenolysis, followed by treatment of the resultant alcohol (IX) with methanesulfonyl chloride provides mesylate (X). The mesylate group of (X) is then displaced with [18F]-potassium fluoride to afford the [18F]-labeled fluoride (XI). Finally, acidic hydrolysis of the N-Boc amino ester (XI) yields the title radiofluorinated compound.

参考文献中间体

合成目标

【1】 Martarello, L.; et al.; Synthesis of syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC9, potential PET ligands for tumor detection. J Med Chem 2002, 45, 11, 2250.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	61667	tert-butyl 2,2,2-trichloroethanimidoate		C₆H₁₀Cl₃NO	详情	详情
(I)	61893	1-[(allyloxy)methyl]benzene; allyl benzyl ether	14593-43-2	C₁₀H₁₂O	详情	详情
(II)	61894	3-[(benzyloxy)methyl]-2,2-dichlorocyclobutanone		C₁₂H₁₂Cl₂O₂	详情	详情
(III)	61895	3-[(benzyloxy)methyl]cyclobutanone		C₁₂H₁₄O₂	详情	详情
(IV)	61896	2-[(benzyloxy)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione		C₁₄H₁₆N₂O₃	详情	详情
(V)	61897	2-[(benzyloxy)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione		C₁₄H₁₆N₂O₃	详情	详情
(VI)	61898	1-amino-3-[(benzyloxy)methyl]cyclobutanecarboxylic acid		C₁₃H₁₇NO₃	详情	详情
(VII)	61899	3-[(benzhydryloxy)methyl]-1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid		C₂₄H₂₉NO₅	详情	详情
(VIII)	61900	tert-butyl 3-[(benzhydryloxy)methyl]-1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylate		C₂₈H₃₇NO₅	详情	详情
(IX)	61942	tert-butyl 1-[(tert-butoxycarbonyl)amino]-3-(hydroxymethyl)cyclobutanecarboxylate		C₁₅H₂₇NO₅	详情	详情
(X)	61943	tert-butyl 1-[(tert-butoxycarbonyl)amino]-3-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate		C₁₆H₂₉NO₇S	详情	详情
(XI)	61944	tert-butyl 1-[(tert-butoxycarbonyl)amino]-3-(fluoromethyl)cyclobutanecarboxylate		C₁₅H₂₆FNO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(A)

The nonradioactive aminoacid is prepared as follows. The Strecker reaction of fluoroacetone (I) with KCN and NH4Cl provides amino nitrile (II). Acid hydrolysis of (II) gives aminoacid (III), which is further protected as the N-Boc derivative (IV) by using di-t-butyl dicarbonate. Treatment of acid (IV) with t-butyl trichloroacetimidate produces the t-butyl ester (V). Subsequent alkylation of (V) with iodomethane and NaH affords the N-methyl derivative (VI). The protecting groups of (VI) are finally removed by acidic hydrolysis to produce the free aminoacid.

参考文献中间体

合成目标

【1】 McConathy, J.; et al.; Radiolabeled amino acids for tumor imaging with PET: Radiosynthesis and biological evaluation of 2-amino-3[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid. J Med Chem 2002, 45, 11, 2240.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	61667	tert-butyl 2,2,2-trichloroethanimidoate		C₆H₁₀Cl₃NO	详情	详情
(I)	61762	Fluoroacetone; 2-Propanone, 1-fluoro-; Fluoroacetone; mono-FLUOROACETONE	430-51-3	C₃H₅FO	详情	详情
(II)	61763	tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate		C₄H₇FN₂	详情	详情
(III)	61764	3-fluoro-2-methylalanine		C₄H₈FNO₂	详情	详情
(IV)	61666	N-(tert-butoxycarbonyl)-3-fluoro-2-methylalanine		C₉H₁₆FNO₄	详情	详情
(V)	61668	tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-fluoro-2-methylpropanoate		C₁₃H₂₄FNO₄	详情	详情
(VI)	61669	tert-butyl 2-[(tert-butoxycarbonyl)(methyl)amino]-3-fluoro-2-methylpropanoate		C₁₄H₂₆FNO₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(A)

The [18F]-labeled compound is prepared as follows. Benzyloxy acetone (I) is treated with KCN and buffered (NH4)2CO3 to produce hydantoin (II). Alkaline hydrolysis of (II), followed by treatment of the crude aminoacid (III) with Boc2O gives the Boc-protected aminoacid (IV). The esterification of (IV) by means of t-butyl trichlroacetimidate affords the t-butyl ester (V), which is N-methylated with MeI and NaH to give compound (VI). Catalytic hydrogenolysis of the benzyl ether group of (VI) yields alcohol (VII). Selective removal of the N-Boc group of (VII) in the presence of the t-butyl ester to furnish (VIII) is achieved with p-toluenesulfonic acid in hot ethanol. Reaction of amino alcohol (VIII) with SOCl2 produces the cyclic sulfamidite (IX), which is further oxidized to sulfamidate (X) with NaIO4 in the presence of a catalytic amount of RuO2. The radiolabeled aminoacid is then obtained by treatment of (X) with [18F]-fluoride, followed by acidic cleavage of the t-butyl ester group.

参考文献中间体

合成目标

【1】 McConathy, J.; et al.; Radiolabeled amino acids for tumor imaging with PET: Radiosynthesis and biological evaluation of 2-amino-3[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid. J Med Chem 2002, 45, 11, 2240.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(A)	61667	tert-butyl 2,2,2-trichloroethanimidoate	C₆H₁₀Cl₃NO	详情	详情
(I)	61670	BENZYLOXYACETONE; (1-BENZYLOXY-2-PROPANONE)	C₁₀H₁₂O₂	详情	详情
(II)	61671	5-[(benzyloxy)methyl]-5-methyl-2,4-imidazolidinedione	C₁₂H₁₄N₂O₃	详情	详情
(III)	61672	O-benzyl-2-methylserine	C₁₁H₁₅NO₃	详情	详情
(IV)	61673	O-benzyl-N-(tert-butoxycarbonyl)-2-methylserine	C₁₆H₂₃NO₅	详情	详情
(V)	61674	tert-butyl 3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-2-methylpropanoate	C₂₀H₃₁NO₅	详情	详情
(VI)	61675	tert-butyl 3-(benzyloxy)-2-[(tert-butoxycarbonyl)(methyl)amino]-2-methylpropanoate	C₂₁H₃₃NO₅	详情	详情
(VII)	61676	tert-butyl 2-[(tert-butoxycarbonyl)(methyl)amino]-3-hydroxy-2-methylpropanoate	C₁₄H₂₇NO₅	详情	详情
(VIII)	61677	tert-butyl 3-hydroxy-2-methyl-2-(methylamino)propanoate	C₉H₁₉NO₃	详情	详情
(IX)	61678	tert-butyl 4-methyl-2-oxo-1,2lambda~4~,3-oxathiazolidine-4-carboxylate	C₈H₁₅NO₄S	详情	详情
(X)	61679	tert-butyl 4-methyl-2,2-dioxo-1,2lambda~6~,3-oxathiazolidine-4-carboxylate	C₈H₁₅NO₅S	详情	详情

Extended Information