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【结 构 式】

【分子编号】26450

【品名】Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid

【CA登记号】15761-38-3

【 分 子 式 】C8H15NO4

【 分 子 量 】189.21144

【元素组成】C 50.78% H 7.99% N 7.4% O 33.82%
与该中间体有关的原料药合成路线共 15 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

该中间体在本合成路线中的序号：(XIV)

The condensation of (XIII) with N-protected L-alanine (XIV) by means of PyBrOP and diethylisopropylamine in DMF gives the cyclic tripeptide (XV), which after deprotection with TFA is condensed with the protected tripeptide (XVI) by means of EDC and HOBT to provide the cyclic hexapeptide (XVII). Finally, this compound is cyclized by hydrolysis of the methyl ester with LiOH in THF/methanol/water, deprotection of the amino group with TFA and cyclization with DPPA and NaHCO3 in DMF.

参考文献 中间体
合成目标
【1】 Bigot, A.; et al.; Total synthesis of an antitumor agent RA-VII via an efficient preparation of cycloisodityrosine. J Org Chem 1999, 64, 17, 6283.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 26446 methyl (9S,12S)-4-methoxy-12-(methylamino)-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C21H24N2O5 详情 详情
(XIV) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(XV) 26447 methyl (9S,12S)-12-[[(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl](methyl)amino]-4-methoxy-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C29H37N3O8 详情 详情
(XVI) 26448 (6R,9S,12S)-12-(4-methoxybenzyl)-2,2,6,9,11-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C22H33N3O7 详情 详情
(XVII) 26449 methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C46H60N6O12 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

Coupling of ethyl glyoxylate derivative (I) with Boc-L-Alanine (II) by means of EDC and DMAP in DMF provides compound (III), whose ethyl ester is subjected to saponification by treatment with NaOH in EtOH to furnish carboxylic acid (IV). Condensation of (IV) with methoxyamine (NH2OMe) in THF/H2O yields methoxyimino acetic acid derivative (V), which is then coupled to pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) in CH2Cl2 by means of phosphorus oxychloride (POCl3) in DMF/EtOAc and N-trimethylsilylacetamide to give compound (VII). Finally, the desired compound is obtained after treatment of (VII) with TFA and anisole in CH2Cl2 for Boc removal . Alternatively, methoxyimino acetic acid derivative (V) can be converted into intermediate (VII) by coupling with 7-amino-3-cephem-4-carboxylic acid (VIII) by means of POCl3 in DMF/EtOAc and N-trimethylsilylacetamide in CH2Cl2 to provide derivative (IX), followed by condensation with iodomethyl pivalate (X) by means of potassium acetate in DMF.

参考文献 中间体
合成目标
【1】 Muro, H.; Kasai, M.; Hatano, s.; Nishimura, K.-I.; Nishizawa, S.; Kakeya, N. (Kyoto Pharmaceutical Industries, Ltd.); Cephalosporin cpds. and production thereof. EP 0497978; JP 1991204883; US 5389625; WO 9106549 .
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) 49506 Ethyl 2-amino-4-thiazoleglyoxylate C7H8N2O3S 详情 详情
(II) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(III) 49507 ethyl 2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-oxoacetate C15H21N3O6S 详情 详情
(IV) 49508 2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-oxoacetic acid C13H17N3O6S 详情 详情
(V) 49509 2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid C14H20N4O6S 详情 详情
(VI) 49510 [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H18N2O5S 详情 详情
(VII) 49511 [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C27H36N6O10S2 详情 详情
(VIII) 49512 (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C7H8N2O3S 详情 详情
(IX) 49513 (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C21H26N6O8S2 详情 详情
(X) 11159 iodomethyl pivalate C6H11IO2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

Coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) and methoxyimino acetic acid derivative (XI) by means of POCl3 and pyridine in CH2Cl2 gives compound (XII) (alternatively (XII) can be obtained by condensation of ceftizoxime (CZX) (XIII) with iodomethyl pivalate (X) in N,N-dimethylacetamide (DMAc) in the presence of dicyclohexylamine). Coupling of (XII) with Boc-L-alanine (II) by means of EDC and DMAP in CH2Cl2 gives intermediate (VII), whose Boc protecting group is removed by treatment with either HCl/isopropanol in formic acid or TFA and anisole in CH2Cl2. Yet another strategy can be followed, involving the coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) with derivative (XIV) by means of Et3N in N,N-dimethylacetamide.

参考文献 中间体
合成目标
【1】 Shirahase, H.; Hatano, S.; Yoshimi, A.; Kitagawa, M.; Kasai, M.; Nishimura, K.; Kakeya, N.; AS-924, a novel bifunctional prodrug of ceftizoxime. J Antibiot 1999, 52, 5, 491.
【2】 Kasai, M.; et al.; AS-924, a novel orally active bifunctional prodrug of ceftizoxime. Synthesis and relationship between physicochemical properties and oral absorption. Chem Pharm Bull 1999, 47, 8, 1081.
【3】 Muro, H.; Kasai, M.; Hatano, s.; Nishimura, K.-I.; Nishizawa, S.; Kakeya, N. (Kyoto Pharmaceutical Industries, Ltd.); Cephalosporin cpds. and production thereof. EP 0497978; JP 1991204883; US 5389625; WO 9106549 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(VI) 49510 [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H18N2O5S 详情 详情
(VII) 49511 [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C27H36N6O10S2 详情 详情
(X) 11159 iodomethyl pivalate C6H11IO2 详情 详情
(XI) 24737 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid 65872-41-5 C6H7N3O3S 详情 详情
(XII) 49514 [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C19H23N5O7S2 详情 详情
(XIII) 49515 (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C13H13N5O5S2 详情 详情
(XIV) 49516 2-(2-[[(2S)-2-aminopropanoyl]amino]-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride C9H11ClN4O3S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XII)

Amino acid (XI) was then coupled with N-Boc-L-alanine (XII) using EDC and HOBt to furnish amide (XIII), and its Boc group was subsequently cleaved with HCl in dioxan, yielding (XIV). A second coupling with N-Boc-L-alanine (XII), followed by acid deprotection gave (XV) as the hydrochloride salt. Conversion to the title methanesulfonate salt was carried out by liberation of the base with NaHCO3 and subsequent treatment with MsOH acetone.

参考文献 中间体
合成目标
【1】 Brighty, K.E. (Pfizer Inc.); Anti-bacterial azabicyclo quinolone carboxylic acids. US 5229396 .
【2】 Brighty, K.E. (Pfizer Inc.); Azabicyclo quinolone and naphthyridone carboxylic acids. US 5164402 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 43089 7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid C20H15F3N4O3 详情 详情
(XII) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(XIII) 43090 7-[(1R,5S)-6-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid C28H28F3N5O6 详情 详情
(XIV) 43091 7-((1R,5S)-6-[[(2S)-2-aminopropanoyl]amino]-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid C23H20F3N5O4 详情 详情
(XV) 43092 7-[(1R,5S)-6-[((2S)-2-[[(2S)-2-aminopropanoyl]amino]propanoyl)amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid C26H25F3N6O5 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

The coupling of 2-amino-4-methylthiophene-3-carboxylic acid ethyl ester (I) with N-(tert-butoxycarbonyl)-L-alanine (II) by means of isobutyl chloroformate and NMM, followed by cyclization with triphenylphosphine in CCl4 gives the thieno-oxazinone (III), which is deprotected with TFA yielding (IV) with a free amino group that is acylated with cinnamic acid by means of DEC and DIEA.

参考文献 中间体
合成目标
【1】 Tew, D.G.; Pinto, I.L.S.M.; Jarvest, R.L.; Jennings, L.J.; Dabrowski, C.E.; Fernandez, A.V.; Lavery, P.; Inhibition of herpes proteases and antiviral activity of 2-substituted thieno[2,3-d]oxazinones. Bioorg Med Chem Lett 1999, 9, 3, 443.
【2】 Jarvest, R.L.; Jennings, L.J.A.; Pinto, I.L. (SmithKline Beecham plc); Thienoxazinone derivs. useful as antiviral agents. WO 9727200 .
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) 29512 ethyl 2-amino-4-methyl-3-thiophenecarboxylate 43088-42-2 C8H11NO2S 详情 详情
(II) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(III) 28659 tert-butyl (1S)-1-(5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazin-2-yl)ethylcarbamate C14H18N2O4S 详情 详情
(IV) 28660 2-[(1S)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one C9H10N2O2S 详情 详情
(V) 10449 (Z)-3-Phenyl-2-propenoic acid 621-82-9 C9H8O2 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 coupling of 2-amino-4-methylthiophene-3-carboxylic acid ethyl ester (I) with N-(tert-butoxycarbonyl)-L-alanine (II) by means of isobutyl chloroformate and NMM, followed by cyclization with triphenylphosphine in CCl4 gives the thieno-oxazinone (III), which is deprotected with TFA yielding (IV) with a free amino group that is acylated with 3-(5-bromothien-2-yl)-2(E)-propenoic acid by means of DEC and DIEA.

参考文献 中间体
合成目标
【1】 Tew, D.G.; Pinto, I.L.S.M.; Jarvest, R.L.; Jennings, L.J.; Dabrowski, C.E.; Fernandez, A.V.; Lavery, P.; Inhibition of herpes proteases and antiviral activity of 2-substituted thieno[2,3-d]oxazinones. Bioorg Med Chem Lett 1999, 9, 3, 443.
【2】 Jarvest, R.L.; Jennings, L.J.A.; Pinto, I.L. (SmithKline Beecham plc); Thienoxazinone derivs. useful as antiviral agents. WO 9727200 .
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) 29512 ethyl 2-amino-4-methyl-3-thiophenecarboxylate 43088-42-2 C8H11NO2S 详情 详情
(II) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(III) 28659 tert-butyl (1S)-1-(5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazin-2-yl)ethylcarbamate C14H18N2O4S 详情 详情
(IV) 28660 2-[(1S)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one C9H10N2O2S 详情 详情
(V) 29513 (E)-3-(5-bromo-2-thienyl)-2-propenoic acid C7H5BrO2S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The cyclization of 2-amino-4-methylthiophene-3-carboxylic acid (I) with N-(tert-butoxycarbonyl)-L-alanine (II), by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (DEC) and HOBT in DMF gives the protected thienooxazinone (III), which is deprotected with trifluoroacetic acid in dichloro methane yielding 2-(1(S)-aminoethyl)-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (IV). Finally, this compound is acylated with 4-oxo-4-phenyl-2(E)-butenoic acid (VI) by means of DEC and diisopropylethylamine in DMF.

参考文献 中间体
合成目标
【1】 Jarvest, R.L.; Pinto, I.L.; Clarke, B.; et al.; Inhibition of human cytomegalovirus protease by enedione derivatives of thieno[2,3-d]oxazinones through a novel dual acylation/alkylation mechanism. Bioorg Med Chem Lett 1999, 9, 3, 449.
【2】 Jarvest, R.L.; Jennings, L.J.A.; Pinto, I.L. (SmithKline Beecham plc); Thienoxazinone derivs. useful as antiviral agents. WO 9727200 .
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) 28658 2-amino-4-methyl-3-thiophenecarboxylic acid C6H7NO2S 详情 详情
(II) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(III) 28659 tert-butyl (1S)-1-(5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazin-2-yl)ethylcarbamate C14H18N2O4S 详情 详情
(IV) 28660 2-[(1S)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one C9H10N2O2S 详情 详情
(V) 28661 (E)-4-oxo-4-phenyl-2-butenoic acid 583-06-2 C10H8O3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(I)

The compound was prepared by solid phase peptide synthesis on a p-methylbenzhydrylamine resin. Attachment of Boc-L-alanine (I) afforded resin (II). Subsequent deprotection of the Boc group of (II) gave the alanine-linked resin (III). Coupling of (III) with Boc-L-proline (IV), followed by Boc group cleavage yielded the dipeptide resin (V). Further coupling of (V) with N-Boc-(2S,3R)-3-amino-2-hydroxy-5-methylhexanoic acid (VI) furnished the tripeptide resin (VI). Finally, deprotection of the Boc group of (VI) and simultaneous cleavage from the resin by treatment with HF provided the title tripeptide amide.

参考文献 中间体
合成目标
【1】 Maggiora, L.L.; Simmons, W.H.; Orawski, A.T.; Apstatin analogue inhibitors of aminopeptidase P, a bradykinin-degrading enzyme. J Med Chem 1999, 42, 13, 2394.
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) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(II) 35168 tert-butyl (1S)-2-amino-1-methyl-2-oxoethylcarbamate C8H16N2O3 详情 详情
(III) 35169 (2S)-2-aminopropanamide C3H8N2O 详情 详情
(IV) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(V) 35170 (2S)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide C8H15N3O2 详情 详情
(VI) 35171 (2S,3R)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoic acid C12H23NO5 详情 详情
(VII) 35172 tert-butyl (1R)-1-[(1S)-2-[(2S)-2-([[(1S)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-1-hydroxy-2-oxoethyl]-3-methylbutylcarbamate C20H36N4O6 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VI)

Coupling of 2,5-dimethylphenol (I) with methyl 3,3-dimethylacrylate (II) by means of methanesulfonic acid yields dihydrocoumarin (III), which is reduced with LiAlH4 in THF to provide alcohol (IV). Selective O-protection at the primary hydroxy group of (IV) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and Et3N in dichloromethane affords compound (V), which is then coupled with Boc-Ala-OH (VI) by means of EDC and DMAP in dichloromethane to give ester (VII). O-Deprotection of (VII) with HOAc in THF/H2O furnishes alcohol (VIII), which is then oxidized by means of pyridinium chlorochromate (PCC) in dichloromethane, giving aldehyde (IX). Compound (IX) is further oxidized with NaClO2 and sodium sulfite (Na2CO3) in H2O and NaH2PO4 in acetonitrile to yield propionic acid (X), whose Boc group is removed by treatment with TFA in dichloromethane, furnishing hydrochloride (XI). Coupling of (XI) with PEG thiazolidinethione (T-PEG) (XII) (1) by means of DIEA in dichloromethane gives PEG-alaninyl derivative (XIII), which is finally condensed with daunorubicin hydrochloride (XIV) by means of EDC · HCl, HOBt and NMM in dichloromethane to afford the target product.

参考文献 中间体
合成目标
【1】 Greenwald, R.B.; et al.; PEG thiazolidine-2-thione, a novel reagent for facile protein modification: Conjugation of bovine hemoglobin. Bioconjugate Chem 1996, 7, 6, 638.
【2】 Choe, Y.H.; Shum, K.; Conover, C.D.; Greenwald, R.B.; Wu, D.; Royzen, M.; Drug delivery systems based on trimethyl lock lactonization: Poly(ethylene glycol) prodrugs of amino-containing compounds. J Med Chem 2000, 43, 3, 475.
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) 46786 3,5-dimethylphenol 108-68-9 C8H10O 详情 详情
(II) 24113 methyl 3-methyl-2-butenoate; Methyl 3,3-dimethylacrylate 924-50-5 C6H10O2 详情 详情
(III) 46787 4,4,5,7-tetramethyl-2-chromanone C13H16O2 详情 详情
(IV) 46788 2-(3-hydroxy-1,1-dimethylpropyl)-3,5-dimethylphenol C13H20O2 详情 详情
(V) 46789 2-(3-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylpropyl)-3,5-dimethylphenol C19H34O2Si 详情 详情
(VI) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(VII) 46790 2-(3-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylpropyl)-3,5-dimethylphenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate C27H47NO5Si 详情 详情
(VIII) 46791 2-(3-hydroxy-1,1-dimethylpropyl)-3,5-dimethylphenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate C21H33NO5 详情 详情
(IX) 46792 2-(1,1-dimethyl-3-oxopropyl)-3,5-dimethylphenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate C21H31NO5 详情 详情
(X) 46793 3-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]oxy)-4,6-dimethylphenyl]-3-methylbutyric acid C21H31NO6 详情 详情
(XI) 46794 3-(2-[[(2S)-2-aminopropanoyl]oxy]-4,6-dimethylphenyl)-3-methylbutyric acid C16H23NO4 详情 详情
(XII) 46795 2-(2-methoxyethoxy)-1-(2-thioxo-1,3-thiazolidin-3-yl)-1-ethanone C8H13NO3S2 详情 详情
(XIII) 46796 3-[2-[((2S)-2-[[2-(2-methoxyethoxy)acetyl]amino]propanoyl)oxy]-4,6-dimethylphenyl]-3-methylbutyric acid C21H31NO7 详情 详情
(XIV) 18598 2-methyl-8-quinolinol 826-81-3 C10H9NO 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XIII)

Azepinone (X) was obtained by cyclization of Boc-L-lysine (IX) in the presence of NaHCO3 and BOP reagent. Subsequent alkylation of the lactam nitrogen of (X) with benzyl bromoacetate (XI) afforded (XII). After Boc deprotection of (XII) with trifluoroacetic acid, coupling with Boc-L-alanine (XIII) gave dipeptide (XIV). This was subjected to a further deprotection and coupling sequence with Boc-L-tryptophan (XV) to give tripeptide (XVI), and then with Boc-L-glutamine (XVII), yielding (XVIII). Acid deprotection of the Boc group of (XVIII), followed by coupling with p-hydroxyphenylpropionic acid (XIX) provided the peptide amide (XX).

参考文献 中间体
合成目标
【1】 Cristau, M.; et al.; Synthesis and biological evaluation of bombesin constrained analogues. J Med Chem 2000, 43, 12, 2356.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 42809 (2S)-6-amino-2-[(tert-butoxycarbonyl)amino]hexanoic acid C11H22N2O4 详情 详情
(X) 42810 L-(-)-N-alpha-Boc-amino-epsilon-caprolactam; tert-butyl (3S)-2-oxoazepanylcarbamate 76944-95-1 C11H20N2O3 详情 详情
(XI) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(XII) 42811 benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-2-oxoazepanyl]acetate n/a C20H28N2O5 详情 详情
(XIII) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(XIV) 42812 benzyl 2-[(3S)-3-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-2-oxoazepanyl]acetate C23H33N3O6 详情 详情
(XV) 16114 N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid 13139-14-5 C16H20N2O4 详情 详情
(XVI) 42813 benzyl 2-[(3S)-3-[((2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl)amino]-2-oxoazepanyl]acetate C34H43N5O7 详情 详情
(XVII) 31820 (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid 13726-85-7 C10H18N2O5 详情 详情
(XVIII) 42814 benzyl 2-((3S)-3-[[(2S,5S,8S)-8-(3-amino-3-oxopropyl)-5-(1H-indol-3-ylmethyl)-2,12,12-trimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-2-oxoazepanyl)acetate C39H51N7O9 详情 详情
(XIX) 25691 3-(4-hydroxyphenyl)propionic acid 501-97-3 C9H10O3 详情 详情
(XX) 42815 benzyl 2-[(3S)-3-[((2S)-2-[[(2S)-2-[((2S)-5-amino-2-[[3-(4-hydroxyphenyl)propanoyl]amino]-5-oxopentanoyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl)amino]-2-oxoazepanyl]acetate C43H51N7O9 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

The reaction of N-(tert-butoxycarbonyl)-L-alanine (I) with biphenyl-4-carbaldehyde (II) by means of oxalyl chloride and ZnCl2 or TsOH gives the oxazolidinone (III), which is alkylated with 4-bromobenzyl bromide (IV) and LHMDS in THF, yielding the alkylated compound (V). The opening of the oxazolidinone ring of (V) with LiOMe and NaHSO3 affords the aminopropionic ester (VI), which is cyclized again with 3,5-dichloroaniline (VII) by means of NaOMe in refluxing toluene to provide imidazolidinedione (VIII). Finally, this compound is methylated with MeI, NaOH and tetrabutylammonium bisulfate to give the target compound.

参考文献 中间体
合成目标
【1】 Farina, V.; Napolitano, E.; Crystallization-induced asymmetric transformations and self-regeneration of stereocenters (SROSC): Enantiospecific synthesis of alpha-benzylalanine and hydantoin BIRT-377. Tetrahedron Lett 2001, 42, 18, 3231.
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) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(II) 28446 [1,1'-biphenyl]-4-carbaldehyde 3218-36-8 C13H10O 详情 详情
(III) 47938 tert-butyl (2S,4S)-2-[1,1'-biphenyl]-4-yl-4-methyl-5-oxo-1,3-oxazolidine-3-carboxylate C21H23NO4 详情 详情
(IV) 16109 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide 589-15-1 C7H6Br2 详情 详情
(V) 47939 tert-butyl (2S,4S)-2-[1,1'-biphenyl]-4-yl-4-(4-bromobenzyl)-4-methyl-5-oxo-1,3-oxazolidine-3-carboxylate C28H28BrNO4 详情 详情
(VI) 47940 methyl (2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]-2-methylpropanoate C16H22BrNO4 详情 详情
(VII) 26542 3,5-dichloroaniline 626-43-7 C6H5Cl2N 详情 详情
(VIII) 47933 (5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione C17H13BrCl2N2O2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

The reaction of N-(tert-butoxycarbonyl)-L-alanine (I) with benzaldehyde dimethylacetal (II) by means of SOCl2 and ZnCl2 gives the oxazolidinone (III), which is alkylated with 4-bromobenzyl bromide (IV) and KHMDS in THF to yield the alkylated compound (V). The opening of the oxazolidinone ring of (V) with HBr/HOAc, followed by esterification with EtOH/HCl, affords the aminopropionic ester (VI), which is cyclized again with 3,5-dichlorophenyl isocyanate (VII) by means of Na2CO3 to provide imidazolidinedione (VIII). Finally, this compound is methylated with Me-I and NaHMDS to give the target compound.

参考文献 中间体
合成目标
【1】 Kapadia, S.R.; et al.; An improved synthesis of chiral alpha-(4-bromobenzyl)alanine ethyl ester and its application to the synthesis of LFA-1 antagonist BIRT-377. J Org Chem 2001, 66, 5, 1903.
【2】 Emeigh, J.E.; et al.; Small molecule antagonists of LFA-1 mediated cell adhesion. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 256.
【3】 Bormann, B.J.; Frye, L.L.; Wu, J.-P.; Kelly, T.A. (Boehringer Ingelheim Pharmaceuticals Inc.); Small molecules useful in the treatment of inflammatory disease. EP 0966447; WO 9839303 .
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) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(II) 27515 Methoxy(phenyl)methyl methyl ether; Dimethylacetal benzaldehyde; Benzaldehyde dimethylacetal 1125-88-8 C9H12O2 详情 详情
(III) 47934 tert-butyl (2S,4S)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate C15H19NO4 详情 详情
(IV) 16109 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide 589-15-1 C7H6Br2 详情 详情
(V) 47935 tert-butyl (2S,4S)-4-(4-bromobenzyl)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate C22H24BrNO4 详情 详情
(VI) 47936 ethyl (2S)-2-amino-3-(4-bromophenyl)-2-methylpropanoate C12H16BrNO2 详情 详情
(VII) 47937 1,3-dichloro-5-isocyanatobenzene; 3,5-dichlorophenyl isocyanate C7H3Cl2NO 详情 详情
(VIII) 47933 (5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione C17H13BrCl2N2O2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VIII)

The condensation between 4-(acetylamino)thiophenol (I) and 5-chloro-2-nitroaniline (II) produced the diaryl sulfide (III). Nitro group reduction in (III) employing SnCl2 gave the phenylenediamine (IV), which was cyclized to the benzimidazole (VI) upon treatment with N,N'-bis(methoxycarbonyl)-S-methylisothiourea (V). Hydrolysis of the acetamido group of (VI) with HCl in MeOH afforded aniline (VII). This was acylated with N-Boc-alanine (VIII) in the presence of EDC to yield amide (IX). The N-Boc protecting group of (IX) was finally removed by treatment with trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Lewis, G.S.; Nolan, J.; Davis, P.D.; Naylor, M.A.; Thomson, P.; Hill, S.A.; Benzimidazole carbamates: A new structural class of vascular targeting agents. Proc Amer Assoc Cancer Res 2001, 42, Abst 2000.
【2】 Davis, P.D. (Angiogene Pharmaceuticals Ltd.); Benzimidazole vascular damaging agents. EP 1140078; WO 0041669 .
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) 34329 N-(4-sulfanylphenyl)acetamide 1126-81-4 C8H9NOS 详情 详情
(II) 15709 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline 1635-61-6 C6H5ClN2O2 详情 详情
(III) 51869 N-[4-[(3-amino-4-nitrophenyl)sulfanyl]phenyl]acetamide C14H13N3O3S 详情 详情
(IV) 51870 N-[4-[(3,4-diaminophenyl)sulfanyl]phenyl]acetamide C14H15N3OS 详情 详情
(V) 28696 methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate C6H10N2O4S 详情 详情
(VI) 51871 methyl 5-[[4-(acetamido)phenyl]sulfanyl]-1H-benzimidazol-2-ylcarbamate C17H16N4O3S 详情 详情
(VII) 51872 methyl 5-[(4-aminophenyl)sulfanyl]-1H-benzimidazol-2-ylcarbamate C15H14N4O2S 详情 详情
(VIII) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(IX) 51873 methyl 5-[[4-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)phenyl]sulfanyl]-1H-benzimidazol-2-ylcarbamate C23H27N5O5S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

Coupling between methyl 2-amino-5-phenylpentanoate (I) and N-Boc-alanine (II) affords dipeptide (III). Deprotection of (III) with trifluoroacetic acid yields amine (IV), which is then acylated with (S)-3,5-difluoromandelic acid (V), producing amide (VI). Finally, ester group reduction using LiBH4 leads to the desired alcohol.

参考文献 中间体
合成目标
【1】 Garofalo, A.W.; et al.; A series of C-terminal amino alcohol dipeptide Abeta inhibitors. 28th Natl Med Chem Symp (June 8 2002, San Diego) 2002, Abst 11.
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) 58436 methyl (2S)-2-amino-5-phenylpentanoate C12H17NO2 详情 详情
(II) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(III) 58437 methyl (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)-5-phenylpentanoate C20H30N2O5 详情 详情
(IV) 58438 methyl (2S)-2-{[(2S)-2-aminopropanoyl]amino}-5-phenylpentanoate C15H22N2O3 详情 详情
(V) 58439 (2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoic acid C8H6F2O3 详情 详情
(VI) 58440 methyl (2S)-2-[((2S)-2-{[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]amino}propanoyl)amino]-5-phenylpentanoate C23H26F2N2O5 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IV)

Racemic amine (I) can be resolved by the following alternative procedures: An alternative procedure to compound (VII) begins by condensating amine (II) with N-Boc-L-alanine (IV) in the presence of HOBt.H2O, DIEA and EDC in THF to yield the N-Boc-L-alaninamide derivative (IX) . Similarly, the hydrochloride of amine (II) reacts with N-Boc-L-alanine (IV) in the presence of HOBt.H2O, DIEA and EDC in THF . Intermediate (IX) is then deprotected with either HCl in EtOAc or 1,4-dioxane , or concentrated HCl , and the resulting amine (VII) is obtained as the free base or employed without isolation, respectively. Finally, either hydrochloride (VII) or the nonisolated species obtained from compound (IX) is condensed with 2(S)-hydroxy-3-methylbutyric acid (X) by means of HOBt.H2O, NMM and EDC.HCl in H2O to give semagacestat . Under related conditions, the free base of (VII) couples with acid (XI) in the presence of HOBt.H2O, DIEA and EDC in THF . Alternatively, silylation of 2(S)-hydroxy-3-methylbutyric acid (X) with HMDS in the presence of (NH4)2SO4 at reflux gives trimethylsilyl 3-methyl-2(S)-(trimethylsilyloxy) butanoate (XI), which is first reacted with (COCl)2 in the presence of DMF in CH2Cl2 and then with the mesylate salt (VIII) by means of NMM in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Koenig, T.M., Nissen, J.S., Mitchell, D. (Eli Lilly and Company). Lactam compound. EP 1345955, JP 2005538031, WO 2002040508.
【2】 Audia, J.E., John, V., Latimer, L.H., Tung, J.S., Nissen, J.S., Thorsett, E.D., McDaniel, S.L. (Eli Lilly and Company; Elan Pharmaceuticals, Inc.). Lactam compound. JP 2004517090, WO 2002047671.
【3】 Koenig, T.M., Audia, J.E., Mitchell, D., Aikins, J.A., Buccilli, L.A., Engel,G.L., McDaniel, S.L. (Eli Lilly and Company). Lactam compound. CA 2425497, EP 1353910, JP 2004521084, WO 2002040451.
【4】 Audia, J.E., Diseroad, B.A., Varghese, J. et al. (Eli Lilly and Company).Lactam compound. US 2007299053, US 7468365.
【5】 Mitchell, D., Hay, L.A., Koenig, T.M., McDaniel, S., Nissen, J.S., Audia, J.E.Classical and dynamic resolution of 1-amino-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one. Tetrahedron Asymmetry 2005, 16(23): 3814-9.
【6】 Pu, Y.J., Vaid, R.K., Boini, S.K., Towsley, R.W., Doecke, C.W., Mitchell, D. A practical method for functionalized peptide or amide bond formation in aqueous-ethanol media with EDC as activator. Org Process Res Dev 2009, 13(2): 310-4.
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) 69307 1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one C11H14N2O 详情 详情
(II) 69308 1(S)-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one C11H14N2O 详情 详情
(III) 69309 1(S)-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one C11H14N2O 详情 详情
(IV) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(V) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(VI) 69310 (S)-2-((tert-butoxycarbonyl)amino)propanoic (isobutyl carbonic) anhydride C13H23NO6 详情 详情
(VII) 69311 (S)-2-amino-N-((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)propanamide hydrochloride C14H19N3O2.HCl 详情 详情
(VIII) 69312 (S)-2-amino-N-((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)propanamide methanesulfonate C14H19N3O2.CH4O3S 详情 详情
(IX) 69313 tert-butyl ((S)-1-(((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)amino)-1-oxopropan-2-yl)carbamate C19H27N3O4 详情 详情
(X) 69314 2(S)-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(XI) 69315 (S)-trimethylsilyl 3-methyl-2-((trimethylsilyl)oxy)butanoate C11H26O3Si2 详情 详情
Extended Information