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【结 构 式】 
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【分子编号】17950 【品名】D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride 【CA登记号】21691-49-6 |
【 分 子 式 】C6H13NO2S 【 分 子 量 】163.24076 【元素组成】C 44.15% H 8.03% N 8.58% O 19.6% S 19.64% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected with HgCl2 and H2S in methanol to furnish the target ester.
| 【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011. |
| 【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 . |
| 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) | 38642 | 2-bromo-1-methyl-4-nitrobenzene | 7745-93-9 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (III) | 38643 | 2-methyl-5-nitro-1,1'-biphenyl | C13H11NO2 | 详情 | 详情 | |
| (IV) | 38644 | 5-nitro[1,1'-biphenyl]-2-carboxylic acid | C13H9NO4 | 详情 | 详情 | |
| (V) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VI) | 38645 | methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate | C19H20N2O5S | 详情 | 详情 | |
| (VII) | 38656 | 2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (VIII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (IX) | 38647 | methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C46H51N3O5S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reductive condensation of N-Boc-L-isoleucinal (I) with glycine methyl ester (II) using sodium triacetoxyborohydride afforded secondary amine (III), which was further reductively condensed with 1-naphthaldehyde (IV), yielding tertiary amine (V). After basic hydrolysis of the methyl ester group of (V), the resulting carboxylic acid (VI) was coupled with L-methionine methyl ester (VII) by means of EDC and HOBt to give peptide (VIII). Subsequent deprotection of the Boc group of (VII) with HCl in cold EtOAc furnished the required intermediate (IX).
| 【1】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 . |
| 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) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 34734 | methyl 2-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]amino)acetate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 34735 | methyl 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetate | C25H36N2O4 | 详情 | 详情 | |
| (VI) | 34736 | 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetic acid | C24H34N2O4 | 详情 | 详情 | |
| (VII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VIII) | 34737 | methyl (6S,12S)-2,2-dimethyl-6-[(1S)-1-methylpropyl]-12-[2-(methylsulfanyl)ethyl]-8-(1-naphthylmethyl)-4,10-dioxo-3-oxa-5,8,11-triazatridecan-13-oate | C30H45N3O5S | 详情 | 详情 | |
| (IX) | 34738 | methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate | C25H37N3O3S | 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 reductive condensation of N-Boc-L-isoleucinal (I) with glycine methyl ester (II) using sodium triacetoxyborohydride afforded secondary amine (III), which was further reductively condensed with 1-naphthaldehyde (IV), yielding tertiary amine (V). After basic hydrolysis of the methyl ester group of (V), the resulting carboxylic acid (VI) was coupled with L-methionine methyl ester (VII) by means of EDC and HOBt to give peptide (VIII). Subsequent deprotection of the Boc group of (VIII) with HCl in cold EtOAc furnished the required intermediate (IX).
| 【1】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 . |
| 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) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 34734 | methyl 2-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]amino)acetate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 34735 | methyl 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetate | C25H36N2O4 | 详情 | 详情 | |
| (VI) | 34736 | 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetic acid | C24H34N2O4 | 详情 | 详情 | |
| (VII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VIII) | 34737 | methyl (6S,12S)-2,2-dimethyl-6-[(1S)-1-methylpropyl]-12-[2-(methylsulfanyl)ethyl]-8-(1-naphthylmethyl)-4,10-dioxo-3-oxa-5,8,11-triazatridecan-13-oate | C30H45N3O5S | 详情 | 详情 | |
| (IX) | 34738 | methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate | C25H37N3O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Treatment of 3-nitro-1,8-naphthalic anhydride (I) with mercuric oxide and aqueous sodium acetate, and then with refluxing concentrated HCl provided a mixture of decarboxylation products (II) and (III). Condensation of this mixture with L-methionine methyl ester (IV) in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, followed by chromatographic separation of isomers, yielded the desired 6-nitronaphthalenecarboxamide (V). Further reduction of the nitro group with SnCl2 in ethanol gave amine (VI), which was reductively condensed with S-triphenylmethyl-N-Boc-cysteinal (VII) in the presence of sodium cyanoborohydride, acetic acid, and molecular sieves to afford (VIII). Then, hydrolysis of methyl ester with lithium hydroxide in THF-water gave acid (IX), and finally, deprotection of trityl and tert-butoxycarbonyl groups with an excess of trifluoroacetic acid in the presence of ethanedithiol provided the title compound as the trifluoroacetate salt.
| 【1】 Ito, Y.; Kato, H.; Yasuda, S.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Benzamide deriv.. EP 0640601; US 5395832; US 5500422; WO 9214705 . |
| 【2】 Baudoin, B.; Burns, C.; Commercon, A.; Guitton, J.-D. (Aventis Pharma SA); Novel farnesyl transferase inhibitors, their preparation and pharmaceutical compsns. containing same. JP 1998501259; WO 9534535 . |
| 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) | 15864 | 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride | 3027-38-1 | C12H5NO5 | 详情 | 详情 |
| (II) | 17948 | 6-nitro-1-naphthoic acid | C11H7NO4 | 详情 | 详情 | |
| (III) | 17949 | 3-nitro-1-naphthoic acid | 4507-84-0 | C11H7NO4 | 详情 | 详情 |
| (IV) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (V) | 17951 | methyl (2S)-4-(methylsulfanyl)-2-[(6-nitro-1-naphthoyl)amino]butanoate | C17H18N2O5S | 详情 | 详情 | |
| (VI) | 17952 | methyl (2S)-2-[(6-amino-1-naphthoyl)amino]-4-(methylsulfanyl)butanoate | C17H20N2O3S | 详情 | 详情 | |
| (VII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (VIII) | 17954 | methyl (2S)-2-[(6-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino]-1-naphthoyl)amino]-4-(methylsulfanyl)butanoate | C44H49N3O5S2 | 详情 | 详情 | |
| (IX) | 17955 | (2S)-2-[(6-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino]-1-naphthoyl)amino]-4-(methylsulfanyl)butyric acid | C43H47N3O5S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected and hydrolyzed first with LiOH and THF and then with TFA and Et3SiH in dichloromethane to furnish the target free acid.
| 【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011. |
| 【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 . |
| 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) | 38642 | 2-bromo-1-methyl-4-nitrobenzene | 7745-93-9 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (III) | 38643 | 2-methyl-5-nitro-1,1'-biphenyl | C13H11NO2 | 详情 | 详情 | |
| (IV) | 38644 | 5-nitro[1,1'-biphenyl]-2-carboxylic acid | C13H9NO4 | 详情 | 详情 | |
| (V) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VI) | 38645 | methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate | C19H20N2O5S | 详情 | 详情 | |
| (VII) | 38656 | 2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (VIII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (IX) | 38647 | methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C46H51N3O5S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)L-5,5-Dimethylthiazolidine-4-carboxylic acid (I) was protected as the N-Boc derivative (II) by treatment with Boc2O and subsequently coupled with L-methionine methyl ester (III) employing EDC and HOBt. The resulting Boc-dipeptide (IV) was then deprotected with trifluoroacetic acid to give (V). On the other hand, Boc-isoleucine (VI) was converted to the N-methoxy amide (VII) by condensation with N,O-dimethylhydroxylamine in the presence of O-benzotriazolyl tetramethyluronium hexafluorophosphate. Reduction of (VII) with LiAlH4 in cold Et2O produced the corresponding aldehyde (VIII). Reductive condensation of thiazolidine (V) with aldehyde (VIII) yielded adduct (IX). The Boc group of (IX) was then deprotected with trifluoroacetic acid to give (X).
| 【1】 Dong, Z.X.; Kim, S.H. (Biomeasure Inc.); Inhibitors of prenyl transferases. WO 9800409 . |
| 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) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (II) | 34777 | (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C11H19NO4S | 详情 | 详情 | |
| (III) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (IV) | 38786 | tert-butyl (4R)-4-([[(1S)-1-(methoxycarbonyl)-3-(methylsulfanyl)propyl]amino]carbonyl)-5,5-dimethyl-1,3-thiazolidine-3-carboxylate | C17H30N2O5S2 | 详情 | 详情 | |
| (V) | 38787 | methyl (2S)-2-([[(4R)-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate | C12H22N2O3S2 | 详情 | 详情 | |
| (VI) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (VII) | 38788 | tert-butyl (1S,2S)-1-[[methoxy(methyl)amino]carbonyl]-2-methylbutylcarbamate | 3350-19-4 | C13H26N2O4 | 详情 | 详情 |
| (VIII) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IX) | 38789 | methyl (2S)-2-[[((4R)-3-[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]-5,5-dimethyl-1,3-thiazolidin-4-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C23H43N3O5S2 | 详情 | 详情 | |
| (X) | 38790 | methyl (2S)-2-[([(4R)-3-[(2S,3S)-2-amino-3-methylpentyl]-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl)amino]-4-(methylsulfanyl)butanoate | C18H35N3O3S2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)5-Bromo-2-furoic acid (I) was converted to the mixed anhydride with isobutyl chloroformate and then reduced to alcohol (II) using NaBH4. After formation of the sodium alkoxide of (II) with NaH, condensation with chloride (III) in the presence of 15-crown-5 provided ether (IV). Hydrolysis of the methyl ester of (IV), followed by coupling of the resulting carboxylic acid (V) with L-methionine methyl ester (VI) gave amide (VII). Further Suzuki coupling of (VII) with 4-chlorophenyl boronic acid (VIII) produced the aryl-substituted furan (IX). Finally, hydrolysis of the methionine methyl ester of (IX) with LiOH, followed by lyophilization furnished the corresponding lithium carboxylate salt.
| 【1】 Augeri, D.J.; Kalvin, D.; Anowick, D.; et al.; Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase. Bioorg Med Chem Lett 1999, 9, 8, 1069. |
| 【2】 Donner, B.G.; Janowick, D.A.; Larsen, J.J.; Rosenberg, S.H.; Hamilton, A.D.; Barr, K.J.; Sorensen, B.K.; Augeri, D.J.; Kalvin, D.M.; O'Connor, S.J.; Fakhoury, S.A.; Swenson, R.E.; Liu, G.; Sebti, S.M.; Shen, W. (University of Pittsburgh); Inhibitors of protein isoprenyl transferases. EP 0986384; WO 9850029; WO 9850030; WO 9850031 . |
| 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) | 31326 | 5-bromo-2-furoic acid | 585-70-6 | C5H3BrO3 | 详情 | 详情 |
| (II) | 31327 | (5-bromo-2-furyl)methanol | C5H5BrO2 | 详情 | 详情 | |
| (III) | 31328 | methyl 5-(chloromethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate | C16H15ClO2 | 详情 | 详情 | |
| (IV) | 31329 | methyl 5-[[(5-bromo-2-furyl)methoxy]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylate | C21H19BrO4 | 详情 | 详情 | |
| (V) | 31330 | 5-[[(5-bromo-2-furyl)methoxy]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylic acid | C20H17BrO4 | 详情 | 详情 | |
| (VI) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VII) | 31331 | methyl (2S)-2-[[(5-[[(5-bromo-2-furyl)methoxy]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C26H28BrNO5S | 详情 | 详情 | |
| (VIII) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (IX) | 31332 | methyl (2S)-2-([[5-([[5-(4-chlorophenyl)-2-furyl]methoxy]methyl)-2'-methyl[1,1'-biphenyl]-2-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate | C32H32ClNO5S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Amide (III) was prepared by acylation of L-methionine methyl ester (I) with 3-(chloromethyl)benzoyl chloride (II). Displacement of the halogen atom of (III) with LiN3 gave azide (IV), which was reduced to amine (V) by catalytic hydrogenation in the presence of Pd/C. Reductive coupling of (V) with protected imidazole-4-carboxaldehyde (VI) provided the (imidazolylmethyl)amine (VII), and a second reductive coupling of (VII) with benzaldehyde (VIII) furnished the trisubstituted amine (IX). The regioselective imidazole alkylation of (IX) with bromide (X), followed by trityl group deprotection with trifluoroacetic acid yielded (XI). Finally, the methyl ester group of (XI) was hydrolyzed with methanolic NaOH to afford the title carboxylic acid.
| 【1】 Ciccarone, T.M.; MacTough, S.C.; Williams, T.M.; et al.; Non-thiol 3-aminomethylbenzamide inhibitor of farnesyl-protein transferase. Bioorg Med Chem Lett 1999, 9, 14, 1991. |
| 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) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (II) | 25107 | 3-(chloromethyl)benzoyl chloride | 63024-77-1 | C8H6Cl2O | 详情 | 详情 |
| (III) | 33729 | methyl (2S)-2-[[3-(chloromethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C14H18ClNO3S | 详情 | 详情 | |
| (IV) | 33730 | methyl (2S)-2-[[3-(azidomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C14H18N4O3S | 详情 | 详情 | |
| (V) | 33731 | methyl (2S)-2-[[3-(aminomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C14H20N2O3S | 详情 | 详情 | |
| (VI) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
| (VII) | 33732 | methyl (2S)-4-(methylsulfanyl)-2-[[3-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]butanoate | C37H38N4O3S | 详情 | 详情 | |
| (VIII) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (IX) | 33733 | methyl (2S)-2-[[3-([(4-cyanobenzyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C45H43N5O3S | 详情 | 详情 | |
| (X) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (XI) | 33734 | methyl (2S)-2-([3-[((4-cyanobenzyl)[[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl]amino)methyl]benzoyl]amino)-4-(methylsulfanyl)butanoate | C34H34N6O3S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VIII)Condensation of 3-aminopyridine (I) with benzaldehyde (II) in refluxing toluene with azeotropic removal of water produced imine (III), which was reduced to amine (IV) using ethanolic NaBH4. Subsequent alkylation of (IV) with methyl 4-bromomethyl-2-(2-methylphenyl)benzoate (V) in the presence of n-BuLi in cold THF yielded the tertiary amine (VI). Basic hydrolysis of the ester group of (VI), followed by EDC-promoted coupling of the resulting carboxylic acid (VII) with L-methionine methyl ester (VIII) afforded amide (IX). The title compound was finally obtained by saponification of the methyl ester group of (IX) by means of LiOH.
| 【1】 Wang, L.; Barr, K.J.; O'Connor, S.; et al.; Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy. J Med Chem 1999, 42, 18, 3701. |
| 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) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 35752 | N-[(Z)-benzylidene]-N-(3-pyridinyl)amine; N-[(Z)-benzylidene]-3-pyridinamine | C12H10N2 | 详情 | 详情 | |
| (IV) | 35753 | N-benzyl-N-(3-pyridinyl)amine; N-benzyl-3-pyridinamine | C12H12N2 | 详情 | 详情 | |
| (V) | 35754 | ethyl 5-(bromomethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate | C17H17BrO2 | 详情 | 详情 | |
| (VI) | 35755 | ethyl 5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylate | C29H28N2O2 | 详情 | 详情 | |
| (VII) | 35756 | 5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylic acid | C27H24N2O2 | 详情 | 详情 | |
| (VIII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (IX) | 35757 | methyl (2S)-2-[[(5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C33H35N3O3S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VII)Palladium-catalyzed coupling of dimethyl iodoterephthalate (I) with 2-methylphenylboronic acid (II) furnished the biphenyl derivative (III). Regioselective ester hydrolysis of (III) under controlled conditions provided the mono acid (IV), which was further reduced to alcohol (V) using borane in THF. After hydrolysis of the remaining ester function of (V), the resulting carboxylic acid (VI) was coupled to L-methionine methyl ester (VII), yielding amide (VIII). Swern oxidation of the alcohol function of (VIII) gave aldehyde (IX). This was then subjected to a reductive amination with amine (X) in the presence of NaBH(OAc)3 to afford the secondary amine (XI). The methyl ester group of (XI) was finally hydrolyzed with LiOH.
| 【1】 Tasker, A.S.; Wasicak, J.; Henry, K.J. Jr.; et al.; PDB-093. Drug Data Rep 1995, 17, 2, 138. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIII) | 43757 | methyl (2S)-2-([[5-(hydroxymethyl)-2'-methyl[1,1'-biphenyl]-2-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate | C21H25NO4S | 详情 | 详情 | |
| (I) | 38996 | dimethyl 2-iodoterephthalate | C10H9IO4 | 详情 | 详情 | |
| (II) | 38997 | 2-methylphenylboronic acid | 16419-60-6 | C7H9BO2 | 详情 | 详情 |
| (III) | 38998 | dimethyl 2'-methyl[1,1'-biphenyl]-2,5-dicarboxylate | C17H16O4 | 详情 | 详情 | |
| (IV) | 38999 | 6-(methoxycarbonyl)-2'-methyl[1,1'-biphenyl]-3-carboxylic acid | C16H14O4 | 详情 | 详情 | |
| (V) | 39000 | methyl 5-(hydroxymethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate | C16H16O3 | 详情 | 详情 | |
| (VI) | 43756 | 5-(hydroxymethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylic acid | C15H14O3 | 详情 | 详情 | |
| (VII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (IX) | 43758 | methyl (2S)-2-[[(5-formyl-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C21H23NO4S | 详情 | 详情 | |
| (X) | 43759 | (2S)-1-cyclohexyl-3-(ethylsulfanyl)-2-propanamine; (1S)-2-cyclohexyl-1-[(ethylsulfanyl)methyl]ethylamine | C11H23NS | 详情 | 详情 | |
| (XI) | 43760 | methyl (2S)-2-[([5-[([(1S)-2-cyclohexyl-1-[(ethylsulfanyl)methyl]ethyl]amino)methyl]-2'-methyl[1,1'-biphenyl]-2-yl]carbonyl)amino]-4-(methylsulfanyl)butanoate | C32H46N2O3S2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XII)Cyclohexylacetic acid (VII) was converted to acid chloride and then condensed with n-butyl amine to give amide (VIII). Reduction of (VIII) with LiAlH4 afforded secondary amine (IX), which was alkylated with bromide (VI) yielding amino ester (X). After basic hydrolysis of the ester group of (X), the resultant carboxylic acid (XI) was coupled with L-methionine methyl ester (XII) to produce amide (XIII). The methyl ester group of (XIII) was finally hydrolyzed by treatment with LiOH.
| 【1】 Donner, B.G.; Janowick, D.A.; Larsen, J.J.; Rosenberg, S.H.; Hamilton, A.D.; Barr, K.J.; Sorensen, B.K.; Augeri, D.J.; Kalvin, D.M.; O'Connor, S.J.; Fakhoury, S.A.; Swenson, R.E.; Liu, G.; Sebti, S.M.; Shen, W. (University of Pittsburgh); Inhibitors of protein isoprenyl transferases. EP 0986384; WO 9850029; WO 9850030; WO 9850031 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 39001 | methyl 5-(bromomethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate | C16H15BrO2 | 详情 | 详情 | |
| (VII) | 39002 | 2-cyclohexylacetic acid | 5292-21-7 | C8H14O2 | 详情 | 详情 |
| (VIII) | 39003 | N-butyl-2-cyclohexylacetamide | C12H23NO | 详情 | 详情 | |
| (IX) | 39004 | N-(2-cyclohexylethyl)-1-butanamine; N-butyl-N-(2-cyclohexylethyl)amine | C12H25N | 详情 | 详情 | |
| (X) | 39005 | methyl 5-[[butyl(2-cyclohexylethyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylate | C28H39NO2 | 详情 | 详情 | |
| (XI) | 39006 | 5-[[butyl(2-cyclohexylethyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylic acid | C27H37NO2 | 详情 | 详情 | |
| (XII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (XIII) | 39007 | methyl (2S)-2-[[(5-[[butyl(2-cyclohexylethyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C33H48N2O3S | 详情 | 详情 |