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【结 构 式】 
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【分子编号】16710 【品名】Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate 【CA登记号】1068-90-2 |
【 分 子 式 】C9H15NO5 【 分 子 量 】217.22184 【元素组成】C 49.76% H 6.96% N 6.45% O 36.83% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of diethyl acetamidomalonate (I) with ethyl 7-bromoheptanoate (II) by means of sodium ethoxide in refluxing ethanol gives diethyl acetamido-(6-ethoxycarbonylhexyl)malonate (III), which is hydrolyzed and decarboxylated with refluxing concentrated HCl yielding 2-aminononanedioic acid (IV). This acid is esterified with SOCl2 and ethanol to the corresponding diethyl ester (V), which is condensed with vinyl cyclohexyl ketone (VI) to afford diethyl 2-[(3-oxo-3-cyclohexylpropyl)amino]nonanedioate (VII). The reaction of (VII) with potassium cyanate in ethanol-HCl gives the corresponding hydantoic ester (VIII), which is cyclized by heating at 100 C affording 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-oxopropyl)hydantoin (IX). Finally, this compound is reduced with NaBH4 in ethanol.
| 【1】 Whittaker, N.; Harris, C.J.; Stepney, R.; Caldwell, A.G.; Heterocyclic prostaglandin analogs. Part 2. Hydantoins and other imidazole analogs. J Chem Soc - Perkins Trans I 1980, 1, 2, 495-505. |
| 【2】 Harris, C.J.; Stepney, R.; Caldwell, A.G.; Whittaker, N.; Hydantoin prostaglandin analog, potemt and selective inhibitors of platelet aggregation. J Chem Soc Chem Commun 1979, 13, 561-562. |
| 【3】 Caldwell, A.G.; Whittaker, N.; US 4204068 . |
| 【4】 Caldwell, A.G.; Whittaker, N.; BE 0876670 . |
| 【5】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; BW-245-C. Drugs Fut 1982, 7, 6, 380. |
| 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) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (II) | 36428 | ethyl 7-bromoheptanoate | 29823-18-5 | C9H17BrO2 | 详情 | 详情 |
| (III) | 36429 | triethyl 1-(acetamido)-1,1,7-heptanetricarboxylate | C18H31NO7 | 详情 | 详情 | |
| (IV) | 36430 | 2-aminononanedioic acid | C9H17NO4 | 详情 | 详情 | |
| (V) | 36431 | diethyl 2-aminononanedioate | C13H25NO4 | 详情 | 详情 | |
| (VI) | 36432 | 1-cyclohexyl-2-propen-1-one | C9H14O | 详情 | 详情 | |
| (VII) | 36433 | diethyl 2-[(3-cyclohexyl-3-oxopropyl)amino]nonanedioate | C22H39NO5 | 详情 | 详情 | |
| (VIII) | 36434 | diethyl 2-[(aminocarbonyl)(3-cyclohexyl-3-oxopropyl)amino]nonanedioate | C23H40N2O6 | 详情 | 详情 | |
| (IX) | 36435 | 7-[3-(3-cyclohexyl-3-oxopropyl)-2,5-dioxo-4-imidazolidinyl]heptanoic acid | C19H30N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 4-(bromomethyl)quinolin-2(1H)-one (I) with diethyl acetamidomalonate (II) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (III), which is submitted to a decarboxylative hydrolysis with refluxing 20% HCl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (IV). Finaily this compound is acylated with 4-chlorobenzoyl chloride by means of K2CO3 in acetone water.
| 【1】 Kanbe, T.; Nakagawa, K.; Morita, S.; Uchida, M.; Komatsu, M.; Tabusa, F.; Studies on 2(1H)-quinolinone derivatives as gastri. Chem Pharm Bull 1985, 33, 9, 3775. |
| 【2】 Uchida, M.; Komatsu, M.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Carbostyril derivs., process for their preparation. DE 3324034; US 4578381 . |
| 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) | 10288 | 4-(Bromomethyl)-2(1H)-quinolinone | C10H8BrNO | 详情 | 详情 | |
| (II) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (III) | 23536 | diethyl 2-(acetamido)-2-[(2-oxo-1,2-dihydro-4-quinolinyl)methyl]malonate | C19H22N2O6 | 详情 | 详情 | |
| (IV) | 10301 | 2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid | C12H12N2O3 | 详情 | 详情 | |
| (V) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The Friedel-Crafts condensation of phenethyl acetate (I) with octanoyl chloride (II) by means of AlCl3 in dichloroethane gives 2-(4-octanoylphenyl)ethyl acetate (III), which is reduced with triethylsilane in TFA to afford 2-(4-octylphenyl)ethyl acetate (IV). The deprotection of (IV) with sodium ethoxide in ethanol gives 2-(4-octylphenyl)ethanol (V), which is treated with methanesulfonyl chloride followed by sodium iodide in refluxing 2-butanone yielding 2-(4-octylphenyl)ethyl iodide (VI). The condensation of (VI) with diethylacetamidomalonate (VII) by means of sodium ethoxide in ethanol/THF gives diethyl 2-acetamido-2-[2-(4-octylphenyl)ethyl]malonate (VIII), which is reduced with LiAlH4 in THF and treated with acetic anhydride in pyridine to afford 2-acetamido-2-(acetoxymethyl)-4-(4-octylphenyl)butyl acetate (IX). The hydrolysis of (IX) with lithium hydroxide in refluxing methanol/water gives 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (X), which is finally treated with HCl in diethyl ether.
| 【1】 Chiba, K.; Adachi, K.; FTY720. Drugs Fut 1997, 22, 1, 18. |
| 【2】 Fujita, T.; Sasaki, S.; Yoneta, M.; Mishina, T.; Adachi, K.; Chiba, K. (Taito Co., Ltd.; Welfide Corporation); 2-Amino-1,3-propanediol compound and immunosuppressant. EP 0627406; JP 1994509845; US 5719176; WO 9408943 . |
| 【3】 Kiuchi, M.; Adachi, K.; Kohara, T.; et al.; Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J Med Chem 2000, 43, 15, 2946. |
| 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) | 16704 | phenethyl acetate; Phenylethyl-(2) Acetate | 103-45-7 | C10H12O2 | 详情 | 详情 |
| (II) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (III) | 16706 | 4-octanoylphenethyl acetate | C18H26O3 | 详情 | 详情 | |
| (IV) | 16707 | 4-octylphenethyl acetate | C18H28O2 | 详情 | 详情 | |
| (V) | 16708 | 2-(4-octylphenyl)-1-ethanol | C16H26O | 详情 | 详情 | |
| (VI) | 16709 | 1-[4-(2-iodoethyl)phenyl]octane | C16H25I | 详情 | 详情 | |
| (VII) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (VIII) | 16711 | diethyl 2-(acetamido)-2-(4-octylphenethyl)malonate | C25H39NO5 | 详情 | 详情 | |
| (IX) | 16712 | 2-(acetamido)-2-[(acetoxy)methyl]-4-(4-octylphenyl)butyl acetate | C25H39NO5 | 详情 | 详情 | |
| (X) | 16713 | 2-amino-2-(4-octylphenethyl)-1,3-propanediol | 162359-55-9 | C19H33NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)A new synthesis of FTY-720 has been described: The Friedel Crafts condensation of octylbenzene (I) with bromoacetyl chloride (II) by means of AlCl3 in dichloromethane gives the phenacyl bromide (III), which is condensed with 2-acetamidomalonic acid diethyl ester (IV) by means of EtONa in ethanol/THF to yielding the ketone-malonic ester adduct (V). Reduction of (V) with Et3SiH by means of TiCl4 in dichloromethane affords compound (VI), which is then reduced with LiAlH4 in THF followed by acetylation with acetic anhydride and pyridine to provide the acetate (VII). Finally, compound (VII) is hydrolyzed with LiOH in refluxing methanol/water and treated with HCl in ethyl ether.
| 【1】 Renault, P.; Durand, P.; Peralba, P.; Sierra, F.; A new efficient synthesis of the immunosuppressive agent FTY-720. Synthesis 2000, 4, 505. |
| 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) | 43807 | 1-octylbenzene | 2189-60-8 | C14H22 | 详情 | 详情 |
| (II) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (III) | 43808 | 2-bromo-1-(4-octylphenyl)-1-ethanone | C16H23BrO | 详情 | 详情 | |
| (IV) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (V) | 43809 | diethyl 2-(acetamido)-2-[2-(4-octylphenyl)-2-oxoethyl]malonate | C25H37NO6 | 详情 | 详情 | |
| (VI) | 16711 | diethyl 2-(acetamido)-2-(4-octylphenethyl)malonate | C25H39NO5 | 详情 | 详情 | |
| (VII) | 16712 | 2-(acetamido)-2-[(acetoxy)methyl]-4-(4-octylphenyl)butyl acetate | C25H39NO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)1) The condensation of S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) with 6-hydroxy-L-norleucine methyl ester (II) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) and hydroxybenzotriazole (HOBT) in dichloromethane gives the corresponding dipeptide (III), which is oxidized with oxalyl chloride in dichloromethane, yielding the aldehyde (IV). The cyclization of (IV) by means of sodium methoxide and trifluoroacetic acid affords the perhydro-pyridothiazepinone (V), which is deprotected with trimethylsilyl iodide (TMS-I) in dichloromethane to give (VI) with a free amino group (1). The acylation of (VI) with 2(S)-(acetylsulfanyl)-3-phenylpropionic acid (VII) by means of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) in dichloromethane yields the corresponding amide (VIII), which is finally deprotected with NaOH in methanol and treated with HCl. 2) The intermediates S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) and 6-hydroxy-L-norleucine (II) have been obtained as follows: 2a) The protection of 3-aminotetrahydrothiophen-2-one (IX) with N-(benzyloxycarbonyloxy)succinimide gives the expected carbamate (X), which is treated first with KOH and then with acetic anhydride, yielding S-acetyl-N-(benzyloxycarbonyl)-DL-homocysteine (XI). Finally, this compound is submitted to optical resolution with (S)-alpha-methylbenzylamine to afford intermediate (I). 2b) The alkylation of acetamidomalonic acid diethyl ester (XII) with 4-acetoxybutyl bromide (XIII) by means of NaH in DMF gives the alkylated ester (XIV), which by a decarboxylative saponification yields 6-acetoxy-DL-norleucine (XV). Optical resolution of (XV) by means of porcine kidney acylase/LiOH in water affords pure 6-hydroxy-L-norleucine (XVI), which is finally esterified with methanol/HCl to intermediate (II).
| 【1】 Robl, J.A.; Sun, C.-Q.; Stevenson, J.; et al.; Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 1997, 40, 11, 1570. |
| 【2】 Graul, A.; Castañer, J.; Leeson, P.; Omapatrilat. Drugs Fut 1999, 24, 3, 269. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 | |
| (I) | 22487 | (2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butyric acid | C14H17NO5S | 详情 | 详情 | |
| (II) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (III) | 22489 | methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-hydroxyhexanoate | C21H30N2O7S | 详情 | 详情 | |
| (IV) | 22490 | methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-oxohexanoate | C21H28N2O7S | 详情 | 详情 | |
| (V) | 22491 | methyl (4S,7S,10aS)-4-[[(benzyloxy)carbonyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C19H24N2O5S | 详情 | 详情 | |
| (VI) | 22492 | methyl (4S,7S,10aS)-4-amino-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C11H18N2O3S | 详情 | 详情 | |
| (VII) | 22493 | (2S)-2-(acetylsulfanyl)-3-phenylpropionic acid | C11H12O3S | 详情 | 详情 | |
| (VIII) | 22494 | methyl (4S,7S,10aS)-4-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C22H28N2O5S2 | 详情 | 详情 | |
| (IX) | 22495 | 3-aminodihydro-2(3H)-thiophenone | 10593-85-8 | C4H7NOS | 详情 | 详情 |
| (X) | 22496 | benzyl 2-oxotetrahydro-3-thiophenylcarbamate | C12H13NO3S | 详情 | 详情 | |
| (XI) | 22497 | acetyl-N-[(benzyloxy)carbonyl]homocysteine | C14H17NO5S | 详情 | 详情 | |
| (XII) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (XIII) | 22499 | 4-bromobutyl acetate | C6H11BrO2 | 详情 | 详情 | |
| (XIV) | 22500 | diethyl 2-(acetamido)-2-[4-(acetoxy)butyl]malonate | C15H25NO7 | 详情 | 详情 | |
| (XV) | 22501 | 6-(acetoxy)norleucine | C8H15NO4 | 详情 | 详情 | |
| (XVI) | 22502 | (2S)-2-amino-6-hydroxyhexanoic acid | 6033-32-5 | C6H13NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The alkylation of diethyl acetamidomalonate (II) with 1-bromo-3-phenylpropane (I) by means of NaOEt provided the substituted malonate (III), which upon hydrolysis and further decarboxylation gave rise to racemic 2-(acetylamino)-5-phenylpentanoic acid (IVa-b). Kinetic resolution employing Acylase I in the presence of CoCl2 produced a mixture of the (S)-amino acid (V) and the unaltered (R)-amide (VI), which were separated by differential solubility. The desired (R)-amide (VI) was hydrolyzed with aqueous HCl and then treated with EtOH to produce aminoester (VII). Subsequent coupling of (VII) with N-Boc-alpha-aminoisobutyric acid (VIII) employing 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) yielded the protected dipeptide (IX). Basic hydrolysis of the ethyl ester of (IX) afforded the intermediate (X).
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa),(VI) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (IVb) | 35775 | (2S)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (I) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (V) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (X) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Alkylation of diethyl acetamidomalonate (I) with 1-bromo-3-phenylpropane (II) in the presence of NaOEt afforded phenylpropyl malonate (III). Hydrolysis and subsequent decarboxylation of malonate ester (III) yielded racemic 2-(acetylamino)-5-phenylpentanoic acid (IV). Kinetic resolution was achieved by enantioselective hydrolysis of the (S)-acetamide to give amino acid (VI). The desired (R)-enantiomer (V) was then hydrolyzed with HCl and further esterified with HCl-EtOH to provide amino ester (VII). Coupling with N-Boc-alpha-aminoisobutyric acid (VIII) via activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine (IX) furnished dipeptide (X). The ethyl ester group of (X) was then hydrolyzed to acid (XI) using LiOH.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 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) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (II) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (IV) | 38799 | N-acetyl-5-phenylnorvaline | C13H17NO3 | 详情 | 详情 | |
| (V) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (VI) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 38798 | 2-chloro-4,6-dimethoxy-1,3,5-triazine; 4-chloro-6-methoxy-1,3,5-triazin-2-yl methyl ether | 3140-73-6 | C5H6ClN3O2 | 详情 | 详情 |
| (X) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (XI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Alkylation of diethyl acetamidomalonate (I) with 1-bromodecane (II) affords malonate (III). Subsequent hydrolysis and decarboxylation of (III) under acidic conditions leads to 2-aminododecanoic acid (IV). This is then protected as the N-Boc derivative (V) upon treatment with Boc2O and NaOH
| 【1】 Blanchfield, J.T.; Dutton, J.L.; Hogg, R.C.; Gallagher, O.P.; Craik, D.J.; Jones, A.; Adams, D.J.; Lewis, R.J..; Alewood, P.F.; Toth, I.; Synthesis, structure elucidation, in vitro biological activity, toxicity, and caco-2 cell permeability of lipophilic analogues of alpha-conotoxin MII. J Med Chem 2003, 46, 7, 1266. |
| 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) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (II) | 58570 | 1-Bromodecane; 1-Decyl bromide; Decyl bromide; n-decyl bromide | 112-29-8 | C10H21Br | 详情 | 详情 |
| (III) | 63516 | diethyl 2-(acetylamino)-2-decylpropanedioate | C19H35NO5 | 详情 | 详情 | |
| (IV) | 63517 | 2-aminododecanoic acid | C12H25NO2 | 详情 | 详情 | |
| (V) | 63518 | 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)dodecanoic acid | C17H33NO4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XXIX)In an alternative route to intermediate (III), ortho-metalation of 1,2-difluorobenzene (XXIV) with n-hexyllithium in THF followed by sequential addition of ZnCl2, CuCl and then chloroacetyl chloride (XXV) gives 2-chloro-2’,3’-difluoroacetophenone (XXVI). Subsequent condensation of chloroketone (XXVI) with vinylmagnesium bromide followed by cyclization of the resulting chlorohydrin (XXVII) under alkaline conditions yields epoxide (XXVIII). This is then coupled with diethyl acetamidomalonate (XXIX) in the presence of Pd(OAc)2 and 1,2-bis(diphenylphosphino)ethane (dppe) to generate the allyl alcohol adduct (XXX), which after conversion to the corresponding mesylate (XXXI) is reacted with 2,2,2-trifluoroethylamine (XXXII) in dimethylacetamide to furnish the allylic amine (XXXIII). Decarbethoxylation of malonate (XXXIII) by heating with LiCl in moist dimethylacetamide provides the N-acetyl aminoester (XXXIV). Then, cyclization of (XXXIV) by means of trifluoroacetic acid in hot toluene gives the azepinone derivative (XXXV). After acidic hydrolysis of acetamide (XXXV), the resulting racemic amine is resolved utilizing (-)-O,O’-di-p-toluoyl-L-tartaric acid (DTTA) in the presence of a trace amount of 5-nitrosalicylaldehyde to provide the (S)-amine ditoluoyltartrate salt (XXXVI). Finally, liberation of the tartrate salt (XXXVI) with HCl in isopropanol and simultaneous hydrogenation of the azepine double bond in the presence of Pd/BaSO4 provides the trans-perhydroazepinone (III) (2-5). Scheme 3.
| 【2】 Palucki, M., Davies, I., Steinhuebel, D., Rosen, J. (Merck & Co., Inc.). Process for the preparation of caprolactam CGRP antagonist intermediate. WO 2007120589. |
| 【3】 McLaughlin, M., Palucki, M., Marcantonio, K. (Merck & Co., Inc.). Process for the preparation of pyridine heterocycle CGRP antagonist intermediate. WO 2007120590. |
| 【4】 Belyk, K., Rivera, N. (Merck & Co., Inc.). Process for the preparation of CGRP antagonist. WO 2007120591. |
| 【5】 Belyk, K. (Merck & Co., Inc.). CGRP antagonist salt. WO 2007120592. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 65556 | (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine | C14H15F5N2O | 详情 | 详情 | |
| (XXIV) | 65570 | 1,2-Difluorobenzene | 367-11-3 | C6H4F2 | 详情 | 详情 |
| (XXV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XXVI) | 65571 | 2-Chloro-2',3'-difluoroacetophenone | C8H5ClF2O | 详情 | 详情 | |
| (XXVII) | 65572 | C10H9ClF2O | 详情 | 详情 | ||
| (XXVIII) | 65573 | C10H8F2O | 详情 | 详情 | ||
| (XXIX) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (XXX) | 65574 | C19H23F2NO6 | 详情 | 详情 | ||
| (XXXI) | 65575 | C20H25F2NO8S | 详情 | 详情 | ||
| (XXXII) | 42542 | 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine | 753-90-2 | C2H4F3N | 详情 | 详情 |
| (XXXIII) | 65576 | C21H25F5N2O5 | 详情 | 详情 | ||
| (XXXIV) | 65577 | C18H21F5N2O3 | 详情 | 详情 | ||
| (XXXV) | 65578 | C16H15F5N2O2 | 详情 | 详情 | ||
| (XXXVI) | 65579 | C14H13F5N2O.C20H18O8 | 详情 | 详情 |