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【结 构 式】

【分子编号】22195

【品名】tert-butyl 1,1-dimethyl-3-oxopropylcarbamate

【CA登记号】

【 分 子 式 】C10H19NO3

【 分 子 量 】201.2658

【元素组成】C 59.68% H 9.52% N 6.96% O 23.85%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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).

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:(VI)

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).

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:(XII)

Amino acid (II) (obtained by N-alkylation of N-Boc-D-phenylalanine (I) with MeI), was coupled to (S)-1-amino-2-propanol (III) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) and 1-hydroxybenzotriazole to give amide (IV). The N-Boc group of (IV) was then deprotected with trifluoroacetic acid in CH2Cl2 to afford (V). Further coupling of (V) with D-naphthylalanine derivative (VI), followed by Boc deprotection with trifluoroacetic acid, provided dipeptide amide (VII). This dipeptide was coupled to intermediate amino acid (VIII) using EDC and 1-hydroxy-7-azabenzotriazole yielding tripeptide (IX). Finally, trifluoroacetic acid-promoted Boc-deprotection of (IX) provided the target compound. Intermediate amino acid (VIII) was prepared from 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (X) upon conversion to the mixed anhydride with ethyl chloroformate, followed by reduction to alcohol (XI) with LiBH4. Subsequent Swern oxidation of the alcohol (XI) furnished aldehyde (XII). This was condensed with triethyl phosphonoacetate, and then saponified with LiOH to produce the intermediate (VIII).

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.
2 Eriksen, E.F.; Kappelgaard, A.-M. (Novo Nordisk A/S); Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis. WO 9746252 .
3 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
10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(I) 22184 (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid C14H19NO4 详情 详情
(II) 22185 (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid 37553-65-4 C15H21NO4 详情 详情
(III) 22186 (S)-(+)-1-Amino-2-propanol; (2S)-1-amino-2-propanol 2799-17-9 C3H9NO 详情 详情
(IV) 22187 tert-butyl (1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl(methyl)carbamate C18H28N2O4 详情 详情
(V) 22188 (2R)-N-[(2S)-2-hydroxypropyl]-2-(methylamino)-3-phenylpropanamide C13H20N2O2 详情 详情
(VI) 22189 (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid 147577-61-5 C19H23NO4 详情 详情
(VII) 22190 (2R)-N-((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide C27H33N3O3 详情 详情
(VIII) 22191 (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid C12H21NO4 详情 详情
(IX) 22192 tert-butyl (E)-5-[[(1R)-2-[((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate C39H52N4O6 详情 详情
(X) 22193 3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XI) 22194 tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate C10H21NO3 详情 详情
(XII) 22195 tert-butyl 1,1-dimethyl-3-oxopropylcarbamate C10H19NO3 详情 详情

合成路线4

该中间体在本合成路线中的序号:(III)

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).

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