Tabimorelin, NNC-26-0703, NN-703, -Drug Synthesis Database

【结构式】

【药物名称】Tabimorelin, NNC-26-0703, NN-703

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

【CA登记号】193079-69-5

【分子式】C₃₂H₄₀N₄O₃

【分子量】528.7006

【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

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

【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

Methylation of N-Boc-D-phenylalanine (VIII) with methyl iodide and NaH afforded the N-methyl amino acid (IX). After coupling with methylamine in the presence of EDC and HOBt, the Boc protecting group of the resulting amide (X) was removed by treatment with trifluoroacetic acid to give (XI). The N-methyl amino acid (XIII), prepared by methylation of N-Boc-naphthylalanine (XII), was then coupled to amine (XI) by means of EDC and HOAt to yield dipeptide amide (XIV). A further treatment of (XIV) with trifluoroacetic acid removed the Boc protecting group to yield (XV), which was then coupled with amino acid (VII) in the presence of EDC and HOAt yielding (XVI). Finally, deprotection of the Boc-tripeptide (XVI) with trifluoroacetic acid provided the title compound.

参考文献中间体

【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
(VII)	22191	(E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid		C₁₂H₂₁NO₄	详情	详情
(VIII)	22184	(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid		C₁₄H₁₉NO₄	详情	详情
(IX)	22185	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid	37553-65-4	C₁₅H₂₁NO₄	详情	详情
(X)	27231	tert-butyl (1R)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate		C₁₆H₂₄N₂O₃	详情	详情
(XI)	27232	(2R)-N-methyl-2-(methylamino)-3-phenylpropanamide		C₁₁H₁₆N₂O	详情	详情
(XII)	23498	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid		C₁₈H₂₁NO₄	详情	详情
(XIII)	22189	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid	147577-61-5	C₁₉H₂₃NO₄	详情	详情
(XIV)	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
(XV)	27234	(2R)-N-[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide		C₂₅H₂₉N₃O₂	详情	详情
(XVI)	27235	tert-butyl (E)-5-[[(1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate		C₃₇H₄₈N₄O₅	详情	详情

合成路线3

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

【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

Extended Information