ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate -Drug Synthesis Database

【结构式】

【分子编号】27230

【品名】ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate

【CA登记号】

【分子式】C₁₄H₂₅NO₄

【分子量】271.35684

【元素组成】C 61.97% H 9.29% N 5.16% O 23.58%

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：(VI)

The intermediate N-Boc-amino acid (VII) was synthesized as shown in Scheme 25409101a. Treatment of 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (I) with ethyl chloroformate and Et3N, followed by reduction of the resulting mixed anhydride (II) with LiBH4, provided alcohol (III). Then, oxidation of (III) under Swern conditions yielded aldehyde (IV). Subsequent Horner-Emmons condensation of (IV) with triethyl phosphonoacetate (V) in the presence of potassium tert-butoxide gave ester (VI), which was saponified with LiOH to provide the required carboxylic acid (VII).

参考文献中间体

合成目标

【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(I)	22193	3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(II)	27229	3-(Tert-butoxycarbonylamino)-3-methyl butyric acid ethoxycarbonyl anhydride		C₁₃H₂₃NO₆	详情	详情
(III)	22194	tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate		C₁₀H₂₁NO₃	详情	详情
(IV)	22195	tert-butyl 1,1-dimethyl-3-oxopropylcarbamate		C₁₀H₁₉NO₃	详情	详情
(V)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(VI)	27230	ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate		C₁₄H₂₅NO₄	详情	详情
(VII)	22191	(E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid		C₁₂H₂₁NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The cyclization of 3-methyl-2-buten-1-ol (I) with acetonitrile (II) gives 2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine (III), which is hydrolyzed with NaOH to yield 3-amino-3-methyl-1-butanol (IV). The protection of the amino group of (IV) with (Boc)2O in isopropanol affords the carbamate (V), which is oxidized at the primary OH group with SO3/pyridine and TEA to provide the aldehyde (VI). The condensation of (VI) with triethyl phosphonoacetate (VII) by means of potassium tert-butoxide in hot toluene gives the desired hexenoic ester (intermediate 27230), which is hydrolyzed with NaOH in refluxing ethanol to yield the corresponding acid intermediate (intermediate 22191).

参考文献中间体

合成目标

【1】 Jessen, C.U.; et al.; Synthesis of N-protected 14C-labelled (2E)-5-amino-5-methylhex-2-enoic acid analogues. J Label Compd Radiopharm 2001, 44, 4, 265.

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)	37754	3-methyl-2-buten-1-ol	556-82-1	C₅H₁₀O	详情	详情
(II)	37210	acetonitrile	75-05-8	C₂H₃N	详情	详情
(III)	46630	2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine		C₇H₁₃NO	详情	详情
(IV)	46631	3-amino-3-methyl-1-butanol		C₅H₁₃NO	详情	详情
(V)	22194	tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate		C₁₀H₂₁NO₃	详情	详情
(VI)	22195	tert-butyl 1,1-dimethyl-3-oxopropylcarbamate		C₁₀H₁₉NO₃	详情	详情
(VII)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(VIII)	27230	ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate		C₁₄H₂₅NO₄	详情	详情
(IX)	22191	(E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid		C₁₂H₂₁NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Reduction of N-Boc-3-amino-3-methylbutanoic acid (I) to alcohol (II) was achieved via formation of the corresponding mixed anhydride with ethyl chloroformate, followed by treatment with LiBH4. Swern oxidation then produced aldehyde (III), which was subjected to a Horner-Emmons condensation with triethyl phosphonoacetate (IV) to afford unsaturated ester (V). Ester hydrolysis with LiOH yielded carboxylic acid (VI). Subsequent alkylation of (VI) with methyl iodide and NaH furnished de N-methyl derivative (VII).

参考文献中间体

合成目标

【1】 Madsen, K.; Kruse hansen, T.; Watson, B.; Peschke, B.; Langeland Johansen, N.; Sehested Hansen, B.; Lau, J.; Thogersen, H.; Ankersen, M.; Petersen, H.; Synthesis and in vitro characterization of new growth hormone secretagogues derived form ipamorelin with dipeptidomimetic N-terminals. Eur J Med Chem 1999, 34, 5, 363.
【2】 Hansen, T.K.; Peschke, B.; Lau, J.; Lundt, B.F.; Ankersen, M.; Watson, B.; Madsen, K. (Novo Nordisk A/S); Cpds. with growth hormone releasing properties. JP 1999209336; JP 1999501054; JP 2000143613; US 6127391; WO 9723508 .

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)	22193	3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(II)	22194	tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate		C₁₀H₂₁NO₃	详情	详情
(III)	22195	tert-butyl 1,1-dimethyl-3-oxopropylcarbamate		C₁₀H₁₉NO₃	详情	详情
(IV)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(V)	27230	ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate		C₁₄H₂₅NO₄	详情	详情
(VI)	22191	(E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid		C₁₂H₂₁NO₄	详情	详情
(VII)	37820	(E)-5-[(tert-butoxycarbonyl)(methyl)amino]-5-methyl-2-hexenoic acid		C₁₃H₂₃NO₄	详情	详情

Extended Information