-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[N-[5-Methyl-5-(methylamino)-2(E)-hexenoyl]-N-methyl-3-(2-naphthyl)-D-alanyl]-N-methyl-D-phenylalanine methylamide

【CA登记号】193079-71-9

【分子式】C₃₃H₄₂N₄O₃

【分子量】542.72769

【开发单位】Novo Nordisk (Originator)

【药理作用】ENDOCRINE DRUGS, Pituitary Disorder Therapy, Treatment of Growth Hormone Deficiency, Treatment of Growth Hormone Secretion Disorders, Growth Hormone Secretagogues

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

合成路线2

The condensation of N-Boc-N-methyl-D-phenylalanine (VIII) with methylamine by means of EDC and HOBt gave the corresponding amide (IX). After acid deprotection of the Boc group of (IX), the resulting amino compound (X) was coupled with N-Boc-N-methyl-D-naphthylalanine (XI) using EDC and HOAt to provide dipeptide (XII). The Boc protecting group of (XII) was further cleaved with trifluoroacetic acid to give (XIII).

参考文献中间体

【1】 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
	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(VIII)	22185	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid	37553-65-4	C₁₅H₂₁NO₄	详情	详情
(IX)	27231	tert-butyl (1R)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate		C₁₆H₂₄N₂O₃	详情	详情
(X)	27232	(2R)-N-methyl-2-(methylamino)-3-phenylpropanamide		C₁₁H₁₆N₂O	详情	详情
(XI)	22189	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid	147577-61-5	C₁₉H₂₃NO₄	详情	详情
(XII)	27233	tert-butyl (1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl(methyl)carbamate		C₃₀H₃₇N₃O₄	详情	详情
(XIII)	27234	(2R)-N-[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide		C₂₅H₂₉N₃O₂	详情	详情

合成路线3

Coupling of amino acid (VII) with dipeptide (XIII) employing EDC and HOAt yielded tripeptide (XIV). The Boc group of (XIV) was then deprotected with trifluoroacetic acid to furnish the title compound.

参考文献中间体

【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	分子式	供应商	用于合成
(VII)	37820	(E)-5-[(tert-butoxycarbonyl)(methyl)amino]-5-methyl-2-hexenoic acid	C₁₃H₂₃NO₄	详情	详情
(XIII)	27234	(2R)-N-[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide	C₂₅H₂₉N₃O₂	详情	详情
(XIV)	27821	(E)-3-(4-hydroxyphenyl)-2-propenamide	C₉H₉NO₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)