tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】40395

【品名】tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate

【CA登记号】

【分子式】C₁₃H₂₆N₂O₄

【分子量】274.36052

【元素组成】C 56.91% H 9.55% N 10.21% O 23.33%

与该中间体有关的原料药合成路线共 6 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5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(VI)

Coupling of threonine benzyl ester (I) to Fmoc-Ile-OH (A) with HBTU, HOBt and DIEA in dichloromethane followed by protection of the hydroxyl group with TBDPS-Cl and imidazole in THF affords protected dipeptide (II). Removal of the Fmoc group of (II) with piperidine/DMF followed by coupling of Fmoc-N-Me-Ile-OH (B) with HBTU, HOBt and DIEA gives fully protected tripeptide (III), which is treated with piperidine/DMF for Fmoc removal and acetylated by means of Ac2O, DIEA in dichloromethane to furnish (IV). Debenzylation of (IV) by hydrogenolysis over Pd/C provides intermediate (V). Addition of 2-bromopropene (VII) and t-BuLi to the Boc-leucine Weinreb amide (VI) in Et2O yields alpha',beta'-unsaturated ketone (VIII), which is oxidized by treatment with H2O2 and DIEA in H2O/benzonitrile/MeOH to afford a mixture of epoxides from which (IX) is separated by column chromatography. Boc deprotection and coupling of peptide (V) with intermediate (IX) by means of TFA, HATU, HOAt, DIEA in dichloromethane, furnishes TBDPS-protected derivative (X), which is finally deprotected by treatment with TBAF in THF.

参考文献中间体

合成目标

【1】 Sin, N.; et al.; Total synthesis of the potent proteasome inhibitor epoxomicin: A useful tool for understanding proteasome biology. Bioorg Med Chem Lett 1999, 9, 15, 2283.

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)	64559	(2S,3S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methylpentanoic acid		C₂₁H₂₃NO₄	详情	详情
(B)	64679	(2S,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-methylpentanoic acid		C₂₂H₂₅NO₄	详情	详情
(I)	43023	benzyl (2S,3R)-2-amino-3-hydroxybutanoate		C₁₁H₁₅NO₃	详情	详情
(II)	43022	benzyl (2S,3R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-[((2S,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylpentanoyl)amino]butanoate		C₄₈H₅₄N₂O₆Si	详情	详情
(III)	43024	benzyl (5S,8S,11S)-11-((1R)-1-[[tert-butyl(diphenyl)silyl]oxy]ethyl)-1-(9H-fluoren-9-yl)-4-methyl-5,8-bis[(1S)-1-methylpropyl]-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate		C₅₅H₆₇N₃O₇Si	详情	详情
(IV)	43025	benzyl (2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(diphenyl)silyl]oxy]butanoate		C₄₂H₅₉N₃O₆Si	详情	详情
(V)	43026	(2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(diphenyl)silyl]oxy]butyric acid		C₃₅H₅₃N₃O₆Si	详情	详情
(VI)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(VII)	42375	2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide	557-93-7	C₃H₅Br	详情	详情
(VIII)	43027	tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate		C₁₄H₂₅NO₃	详情	详情
(IX)	43028	tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；tert-butyl (1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butylcarbamate		C₁₄H₂₅NO₄	详情	详情
(X)	43029	(2S,3S)-2-[acetyl(methyl)amino]-N-((1S,2S)-1-[[((1S,2R)-2-[[tert-butyl(diphenyl)silyl]oxy]-1-[[((1R)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl)amino]carbonyl]propyl)amino]carbonyl]-2-methylbutyl)-3-methylpentanamide		C₄₄H₆₈N₄O₇Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The reaction of N-(tert-butoxycarbonyl)-L-leucine (I) with N,O-dimethylhydroxylamine and HBTU in DMF gives the corresponding methoxyamide (II), which is reduced with LiAlH4 in ethyl ether yielding the aldehyde (III). The reductocondensation of (III) with the piperidine (IV) by means of sodium triacetoxyborohydride in dichloromethane affords the protected adduct (V), which is finally deprotected with TFA in dichloromethane. The intermediate piperidine (IV) has been obtained as follows: The reductocondensation of the piperidinone (VI) with 4-(benzyloxy)aniline (VII) by means of sodium triacetoxyborohydride in dichloromethane gives the secondary amine (VIII), which is alkylated with 3-methyl-2-butenyl bromide (IX) and DIPEA in THF yielding the protected piperidine (IX). Finally, this compound is deprotected with TFA in dichloromethane to afford the target intermediate (IV).

参考文献中间体

合成目标

【1】 Siebers, K.M.; Hu, L.-Y.; Rafferty, M.F.; et al.; Neuronal N-type calcium channel blocker: Structure-activity relationship of a series of (S)-2-amino-1(4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl)-4-methyl-pentan-1-one analogs. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 259.
【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 .

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)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(II)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(III)	27058	tert-butyl (1S)-1-formyl-3-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(IV)	38232	N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine		C₂₃H₃₀N₂O	详情	详情
(V)	40394	tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]methyl)-3-methylbutylcarbamate		C₃₄H₅₁N₃O₃	详情	详情
(VI)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(VII)	22460	4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(VIII)	38230	tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate		C₂₃H₃₀N₂O₃	详情	详情
(IX)	12989	4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene	870-63-3	C₅H₉Br	详情	详情
(X)	38231	tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate		C₂₈H₃₈N₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).

参考文献中间体

合成目标

【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Va)	40625	ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate		C₁₆H₂₇NO₅	详情	详情
(Vb)	40626	ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate		C₁₆H₂₇NO₅	详情	详情
(VIa)	40627	tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate		C₁₄H₂₅NO₄	详情	详情
(VIb)	40628	tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate		C₁₄H₂₅NO₄	详情	详情
(I)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(II)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(III)	27058	tert-butyl (1S)-1-formyl-3-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(IV)	35333	ethyl propiolate	623-47-2	C₅H₆O₂	详情	详情
(VII)	40629	tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate		C₁₅H₂₇NO₄	详情	详情
(VIII)	40630	(2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid		C₁₅H₂₉NO₅	详情	详情
(IX)	40631	(2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid		C₂₁H₄₃NO₅Si	详情	详情
(X)	40632	(2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid		C₁₆H₃₅NO₃Si	详情	详情
(XI)	40633	(2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid		C₃₁H₄₅NO₅Si	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Va)	40625	ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate		C₁₆H₂₇NO₅	详情	详情
(Vb)	40626	ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate		C₁₆H₂₇NO₅	详情	详情
(VIa)	40627	tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate		C₁₄H₂₅NO₄	详情	详情
(VIb)	40628	tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate		C₁₄H₂₅NO₄	详情	详情
(I)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(II)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(III)	27058	tert-butyl (1S)-1-formyl-3-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(IV)	35333	ethyl propiolate	623-47-2	C₅H₆O₂	详情	详情
(VII)	40629	tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate		C₁₅H₂₇NO₄	详情	详情
(VIII)	40630	(2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid		C₁₅H₂₉NO₅	详情	详情
(IX)	40631	(2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid		C₂₁H₄₃NO₅Si	详情	详情
(X)	40632	(2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid		C₁₆H₃₅NO₃Si	详情	详情
(XI)	40633	(2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid		C₃₁H₄₅NO₅Si	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

Butylmagnesium bromide (II) was added to the Weinreb amide of Boc-L-leucine (I), yielding ketone (III), which was further reduced with NaBH4 to give alcohol (IV) as a diastereomeric mixture. The Boc protecting group of (IV) was removed employing trifluoroacetic acid in CH2Cl2, and the resulting amino alcohol (V) was coupled with N-Boc-L-histidine (VI) by means of BOP reagent to afford amide (VII). Deprotection of the Boc group of (VII) with trifluoroacetic acid then furnished the target C-terminal fragment (VIII).

参考文献中间体

合成目标

【1】 Cristau, M.; et al.; Synthesis and biological evaluation of bombesin constrained analogues. J Med Chem 2000, 43, 12, 2356.

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)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(II)	42802	bromo(butyl)magnesium	693-03-8	C₄H₉BrMg	详情	详情
(III)	42803	tert-butyl (1S)-1-isobutyl-2-oxohexylcarbamate		C₁₅H₂₉NO₃	详情	详情
(IV)	42804	tert-butyl (1S)-2-hydroxy-1-isobutylhexylcarbamate		C₁₅H₃₁NO₃	详情	详情
(V)	42805	(4S)-4-amino-2-methyl-5-nonanol		C₁₀H₂₃NO	详情	详情
(VI)	42808	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-imidazol-5-yl)propionic acid	17791-52-5	C₁₁H₁₇N₃O₄	详情	详情
(VII)	42806	tert-butyl (1S)-2-[[(1S)-2-hydroxy-1-isobutylhexyl]amino]-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate		C₂₁H₃₈N₄O₄	详情	详情
(VIII)	42807	(2S)-2-amino-N-[(1S)-2-hydroxy-1-isobutylhexyl]-3-(1H-imidazol-5-yl)propanamide		C₁₆H₃₀N₄O₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(XXVII)

Condensation of N-Boc-leucine (X) with N,O-dimethylhydroxylamine hydrochloride by means of i-BuOCOCl, NMM and Et3N in CH2Cl2 gives N-Boc-L-leucine Weinreb amide (XXVII) , which is then coupled with isopropenyl magnesium bromide (XXVIII) in THF (1) or 2-bromopropene (XXIX) in the presence of BuLi in Et2O at –78 °C to yield the heptenone derivative (XXX) . Reduction of heptenone (XXX) with NaBH4 and CeCl3·7H2O in MeOH results in a diastereomeric mixture of allylic alcohols (XXXIa) and (XXXIb), which is then epoxidized by treatment with mCPBA in CH2Cl2 to afford a mixture of oxiranes (XXXIIa) and (XXXIIb). Finally, this mixture is oxidized with Dess Martin periodinane in acetonitrile, followed by chromatographic separation . Compound (XXVI) can also be prepared by epoxidation of heptenone derivative (XXX) with H2O2 in the presence of PhCN and DIEA in MeOH or NaOCl in pyridine or Ca(OCl)2 in NMP , followed by separation by means of column chromatography .

参考文献中间体

合成目标

【2】 Sin, N., Kim, K.B., Elofsson, M., Meng, L., Auth, H., Kwok, B.H.B., Crews, C.M. Total synthesis of the potent proteasome inhibitor epoximicin: A useful tool for understanding proteosome biology. Bioorg Med Chem Lett 1999, 9(15): 2283-8.
【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXIa)	69411	tert-butyl ((3S,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate		C₁₄H₂₇NO₃	详情	详情
(XXXIb)	69412	tert-butyl ((3R,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate		C₁₄H₂₇NO₃	详情	详情
(XXXIIa)	69413	tert-butyl ((1R,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate		C₁₄H₂₇NO₄	详情	详情
(XXXIIb)	69414	tert-butyl ((1S,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate		C₁₄H₂₇NO₄	详情	详情
(X)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(XXVI)	43028	tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；tert-butyl (1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butylcarbamate		C₁₄H₂₅NO₄	详情	详情
(XXVII)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(XXVIII)	43649	bromo(isopropenyl)magnesium；isopropenyl magnesium bromide；1-Methylvinylmagnesiumbromide;1-Propen-2-ylmagnesium bromide;a-Methylvinylmagnesium bromide	13291-18-4	C₃H₅BrMg	详情	详情
(XXIX)	42375	2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide	557-93-7	C₃H₅Br	详情	详情
(XXX)	43027	tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate		C₁₄H₂₅NO₃	详情	详情

Extended Information