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【结 构 式】 
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【分子编号】22191 【品名】(E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid 【CA登记号】 |
【 分 子 式 】C12H21NO4 【 分 子 量 】243.30308 【元素组成】C 59.24% H 8.7% N 5.76% O 26.3% |
合成路线1
该中间体在本合成路线中的序号：(VII)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：(VII)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.
| 【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
该中间体在本合成路线中的序号：(IX)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4
该中间体在本合成路线中的序号：(IX)N-Boc-N-Methyl-D-phenylalaninol (I) was oxidized to aldehyde (II) using SO3-pyridine complex. Reductive amination of (II) with benzylamine to yield (III), followed by hydrogenolytic debenzylation then furnished the monoprotected diamine (IV). This was condensed with methanesulfonyl chloride to yield sulfonamide (V). After deprotection of the Boc group of (V) with trifluoroacetic acid, amine (VI) was coupled with N-Boc-N-methyl-D-naphthylalanine (VII) using EDC and HOAt. The resulting amide (VIII) was further deprotected with trifluoroacetic acid, and then coupled with 5-(tert-butoxycarbonyl)amino-5-methyl-2-hexenoic acid (IX) to yield (X). Finally, acid deprotection of the Boc group of (X) furnished the target compound.
| 【1】 Hansen, B.S.; Peschke, B.; New growth hormone secretagogues: C-terminal modified sulfonamide-analogues of NN703. Bioorg Med Chem Lett 1999, 9, 9, 1295. |
| 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) | 25300 | tert-butyl (1R)-1-benzyl-2-hydroxyethyl(methyl)carbamate | C15H23NO3 | 详情 | 详情 | |
| (II) | 25301 | tert-butyl (1R)-1-benzyl-2-oxoethyl(methyl)carbamate | C15H21NO3 | 详情 | 详情 | |
| (III) | 25302 | tert-butyl (1R)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate | C22H30N2O2 | 详情 | 详情 | |
| (IV) | 25303 | tert-butyl (1R)-2-amino-1-benzylethyl(methyl)carbamate | C15H24N2O2 | 详情 | 详情 | |
| (V) | 25304 | tert-butyl (1R)-1-benzyl-2-[(methylsulfonyl)amino]ethyl(methyl)carbamate | C16H26N2O4S | 详情 | 详情 | |
| (VI) | 25305 | N-[(2R)-2-(methylamino)-3-phenylpropyl]methanesulfonamide | C11H18N2O2S | 详情 | 详情 | |
| (VII) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
| (VIII) | 25306 | tert-butyl (1R)-2-[[(1R)-1-benzyl-2-[(methylsulfonyl)amino]ethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl(methyl)carbamate | C30H39N3O5S | 详情 | 详情 | |
| (IX) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (X) | 25307 | tert-butyl (E,7R,10R)-10-benzyl-1,1,6,9-tetramethyl-7-(2-naphthylmethyl)-5,8,13,13-tetraoxo-13lambda(6)-thia-6,9,12-triaza-3-tetradecen-1-ylcarbamate | C37H50N4O6S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)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6
该中间体在本合成路线中的序号：(VI)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 |
合成路线7
该中间体在本合成路线中的序号：(VIII)The title compound was prepared by stepwise peptide synthesis starting from N-Fmoc-N-methyl-D-thienylalanine (I), which was condensed with trimethyl hydrazine (II) to give hydrazide (III). Removal of the Fmoc protecting group with piperidine in DMF provided amine (IV), which was subsequently coupled with N-methyl-D-naphthylalanine (V) in the presence of EDC and HOAt to furnish the dipeptide hydrazide (VI). After removal of the Fmoc group of (VI) with piperidine, the resulting amine (VII) was coupled with N-Boc-5-amino-5-methylhex-2-enoic acid (VIII), yielding amide (IX). Final deprotection of the Boc group of (IX) using trifluoroacetic acid afforded the title compound.
| 【1】 Hansen, B.S.; Ankersen, M.; Nielsen, K.K.; Hansen, T.K.; Raun, K.; Growth hormone secretagogues derived from NN703 with hydrazides as c-terminal. Eur J Med Chem 2000, 35, 5, 487. |
| 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) | 42289 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-(2-thienyl)propionic acid | C23H21NO4S | 详情 | 详情 | |
| (II) | 42290 | 1,1,2-trimethylhydrazine | C3H10N2 | 详情 | 详情 | |
| (III) | 42291 | 9H-fluoren-9-ylmethyl methyl[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]carbamate | C26H29N3O3S | 详情 | 详情 | |
| (IV) | 42292 | (2R)-N,N',N'-trimethyl-2-(methylamino)-3-(2-thienyl)propanohydrazide | C11H19N3OS | 详情 | 详情 | |
| (V) | 42293 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-(2-naphthyl)propionic acid | C29H25NO4 | 详情 | 详情 | |
| (VI) | 42294 | 9H-fluoren-9-ylmethyl methyl[(1R)-2-[methyl[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]amino]-1-(2-naphthylmethyl)-2-oxoethyl]carbamate | C40H42N4O4S | 详情 | 详情 | |
| (VII) | 42295 | (2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]propanamide | C25H32N4O2S | 详情 | 详情 | |
| (VIII) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (IX) | 42296 | tert-butyl (E)-1,1-dimethyl-5-[methyl[(1R)-2-[methyl[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]amino]-1-(2-naphthylmethyl)-2-oxoethyl]amino]-5-oxo-3-pentenylcarbamate | C37H51N5O5S | 详情 | 详情 |