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【结 构 式】 
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【分子编号】18843 【品名】(2S)-2-amino-N,3,3-trimethylbutanamide 【CA登记号】89226-12-0 |
【 分 子 式 】C7H16N2O 【 分 子 量 】144.21692 【元素组成】C 58.3% H 11.18% N 19.42% O 11.09% |
合成路线1
该中间体在本合成路线中的序号：(IX)Treatment of butanedioate derivative (I) with methallyl iodide (II) and LDA in THF affords alkene (III), which is then reduced by hydrogenation over Pd/C and subjected to saponification by means of KOH in dioxane to yield succinic acid (IV). Protection of (IV) with 2,2-dimethoxypropane (V) and p-TsOH in DMF provides derivative (VI), which is then coupled with pentafluorophenol (VII) by using EDC in CH2Cl2 to furnish activated ester (VIII). Displacement of the pentafluorophenol moiety of (VIII) by treatment with L-tert-leucine methylamide (IX) in DMF gives methylamide derivative (X), which is deprotected with THF and HCl and condensed with O-benzylhydroxylamine (XI) by means of EDC to afford derivative (XII). Finally, (XII) is debenzylated by hydrogenation over Pd/C in EtOH to give the target compound.
| 【1】 Davenport, R.J.; Watson, R.J.; An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat. Tetrahedron Lett 2000, 41, 41, 7983. |
| 【2】 Dickens, J.P.; Crimmin, M.J.; Beckett, R.P. (British Biotech plc); Natural amino acid derivs. as metalloproteinase inhibitors. EP 0651738; EP 0651739; GB 2268933; GB 2268934; JP 1995509460; JP 1998204081; WO 9402446; WO 9402447 . |
| 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) | 43782 | diisopropyl (2S)-2-hydroxybutanedioate | C10H18O5 | 详情 | 详情 | |
| (II) | 43783 | 3-iodo-2-methyl-1-propene | C4H7I | 详情 | 详情 | |
| (III) | 43784 | diisopropyl (2S,3R)-2-hydroxy-3-(2-methyl-2-propenyl)butanedioate | C14H24O5 | 详情 | 详情 | |
| (IV) | 43785 | (2S,3R)-2-hydroxy-3-isobutylbutanedioic acid | C8H14O5 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 43786 | (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid | C11H18O5 | 详情 | 详情 | |
| (VII) | 22662 | 2,3,4,5,6-pentafluorophenol | 771-61-9 | C6HF5O | 详情 | 详情 |
| (VIII) | 43787 | 2,3,4,5,6-pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate | C17H17F5O5 | 详情 | 详情 | |
| (IX) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (X) | 43788 | (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide | C18H32N2O5 | 详情 | 详情 | |
| (XI) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XII) | 43789 | (2S,3R)-N(1)-(benzyloxy)-N(4)-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-hydroxy-3-isobutylbutanediamide | C22H35N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)An improved method for the obtaining of the desired product is the direct coupling of carboxylic acid derivative (VI) with L-tert-leucine methylamide (IX) by using EDC in CH2Cl2 to furnish methylamide derivative (X), followed by final treatment of (X) with hydroxylamine (NH2OH) in THF.
| 【1】 Davenport, R.J.; Watson, R.J.; An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat. Tetrahedron Lett 2000, 41, 41, 7983. |
| 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) | 43876 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]h | C56H66Cl3NO16Si | 详情 | 详情 | |
| (IX) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (X) | 43788 | (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide | C18H32N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The alkylation of 4(S)-benzyl-3-nonanoyloxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopropylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is treated with dimethylamine and cyanophosphonic acid diethyl ester yielding the dimethylamide (IV). The iodination of (IV) with I2/dimethoxyethane (DME) with simultaneous cyclization yields 3(R)-heptyl-5(S)-(iodomethyl)tetrahydrofuran-2-one (V). The condensation of (V) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid (TFA) affords 3(R)-heptyl-5(S)-(tritylsulfanylmethyl)tetrahydrofuran-2-one (VI). The ring opening of (VI) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives 4(S)-(tert-butyldimethyl-silyloxy)-2(R)-heptyl-5-(tritylsulfanyl)pentanoic acid (VII), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VIII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-heptyl-4-(S)-hydroxy-5-(tritylsulfanyl)pentanamido]-N,3,3-trimethylbutyramide (IX). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target compound (X).
| 【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (I) | 27010 | (4S)-4-benzyl-3-nonanoyl-1,3-oxazolidin-2-one | C19H27NO3 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 27011 | (2R)-2-hexyl-4-pentenoic acid | C11H20O2 | 详情 | 详情 | |
| (IV) | 27012 | (2R)-2-hexyl-N,N-dimethyl-4-pentenamide | C13H25NO | 详情 | 详情 | |
| (V) | 27013 | (3R,5S)-3-heptyl-5-(iodomethyl)dihydro-2(3H)-furanone | C12H21IO2 | 详情 | 详情 | |
| (VI) | 27014 | (3R,5S)-3-heptyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone | C31H36O2S | 详情 | 详情 | |
| (VII) | 27015 | (2R)-2-[(2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(tritylsulfanyl)propyl]nonanoic acid | C37H52O3SSi | 详情 | 详情 | |
| (VIII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (IX) | 27016 | (2R)-2-[(2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(tritylsulfanyl)propyl]-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]nonanamide | C44H66N2O3SSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target compound.
| 【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (I) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 26985 | (2R)-2-isobutyl-4-pentenoic acid | C9H16O2 | 详情 | 详情 | |
| (IV) | 27021 | (3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone | C9H15IO2 | 详情 | 详情 | |
| (V) | 27022 | (3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone | C28H30O2S | 详情 | 详情 | |
| (VI) | 27023 | (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid | C34H46O3SSi | 详情 | 详情 | |
| (VII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (VIII) | 27024 | (2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide | C35H46N2O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is treated with dimethylamine and cyanophosphonic acid diethyl ester yielding the dimethylamide (IV). The iodination of (IV) with I2/dimethoxyethane (DME) with simultaneous cyclization yields 5(S)-(iodomethyl)-3(R)-isobutyltetrahydrofuran-2-one (V). The condensation of (V) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and TFA affords 3(R)-isobutyl-5(S)-(triphenylmethylsulfanylmethyl)tetrahydrofuran-2-one (VI). The ring opening of (VI) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives 4(S)-(tert-butyldimethylsilyloxy)-2(R)-isobutyl-5-(tritylsulfanyl)pentanoic acid (VII), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VIII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(S)-hydroxy-5-(tritylsulfanyl)pentanamido]-N,3,3-trimethylbutyramide (IX). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target campound (X).
| 【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (I) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 26985 | (2R)-2-isobutyl-4-pentenoic acid | C9H16O2 | 详情 | 详情 | |
| (IV) | 26986 | (2R)-2-isobutyl-N,N-dimethyl-4-pentenamide | C11H21NO | 详情 | 详情 | |
| (V) | 26987 | (3R,5S)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone | C9H15IO2 | 详情 | 详情 | |
| (VI) | 26988 | (3R,5S)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone | C28H30O2S | 详情 | 详情 | |
| (VII) | 26989 | (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid | C34H46O3SSi | 详情 | 详情 | |
| (VIII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (IX) | 26990 | (2R,4S)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide | C35H46N2O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)The alkylation of 4(S)-benzyl-3-nonanoyloxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopropylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-3-heptyl-5-(iodomethyl)tetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid (TFA) affords (R,R)-3-heptyl-5-(triphenylmethyl-sulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-heptyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-heptyl-4(R)-hydroxy-5-(tritylsulfanyl)pentanamido]-N,3,3-trimethylbutyramide (VIII). Finally, compound (VIII) is oxidized with TFA, pyridine, DMSO and EDC, and detritylated with TFA to give the target compound.
| 【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (I) | 27010 | (4S)-4-benzyl-3-nonanoyl-1,3-oxazolidin-2-one | C19H27NO3 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 27011 | (2R)-2-hexyl-4-pentenoic acid | C11H20O2 | 详情 | 详情 | |
| (IV) | 27017 | (3R,5R)-3-heptyl-5-(iodomethyl)dihydro-2(3H)-furanone | C12H21IO2 | 详情 | 详情 | |
| (V) | 27018 | (3R,5R)-3-heptyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone | C31H36O2S | 详情 | 详情 | |
| (VI) | 27019 | (2R)-2-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(tritylsulfanyl)propyl]nonanoic acid | C37H52O3SSi | 详情 | 详情 | |
| (VII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (VIII) | 27020 | (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(2R)-2-hydroxy-3-(tritylsulfanyl)propyl]nonanamide | C38H52N2O3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, compound (VIII) is oxidized with TFA, pyridine, DMSO and EDC, and detritylated with TFA to give the target compound.
| 【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (I) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 26985 | (2R)-2-isobutyl-4-pentenoic acid | C9H16O2 | 详情 | 详情 | |
| (IV) | 27021 | (3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone | C9H15IO2 | 详情 | 详情 | |
| (V) | 27022 | (3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone | C28H30O2S | 详情 | 详情 | |
| (VI) | 27023 | (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid | C34H46O3SSi | 详情 | 详情 | |
| (VII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (VIII) | 27024 | (2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide | C35H46N2O3S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVII)Title compound has been prepared by several related ways. Alkylation of methyl acetoacetate (I) with n-heptyl bromide (II) in the presence of NaOMe in refluxing MeOH yielded (III), which was brominated in CHCl3 at 0 C to give (IV). Subsequent reaction with triphenylmethyl mercaptan (V) and tetrabutyl ammonium hydroxide in toluene at r.t. provided (XI). Alternatively, beta-ketoester (XI) was prepared from a-mercaptoacetic acid (VI). Thus, protection as the S-trityl compound (VIII) by treatment with triphenylcarbinol (VII) and TFA, followed by condensation with N,O-dimethyl hydroxylamine in the presence of EDC and HOBt afforded N-methoxyamide (IX). Then, Claisen condensation with methyl nonanoate (X) using LDA as the base in THF at -78 C provided ketoester (XI). In order to avoid b-ketoacid decarboxylation, ketone (XI) was reduced to alcohol (XV) with NaBH4 in MeOH at 0 C. This hydroxyester was also prepared by a related route, consisting of protection of methyl mercaptoacetate (XII) as the S-trityl compound (XIII), followed by reduction to aldehyde (XIV) with DIBAL-H and condensation with methyl nonanoate (X). Saponification of methyl ester (XV) with KOH yielded hydroxyacid (XVI). Subsequent coupling with tert-butylglycine amide (XVII) using EDC and HOBt as the condensing agents produced amide (XVIII). Ketoamide (XX) was then obtained by oxidation with Dess-Martin periodinane (XIX). Finally, deprotection of the S-trityl group was effected by trifluoroacetic acid treatment under reducing conditions with triethyl silane to provide the target compound.
| 【1】 Campbell, D.A.; Xiao, X.Y.; Harris, D.; Ida, S.; Mortezaei, R.; Ngu, K.; Shi, L.; Tien, D.; Wang, Y.; Navre, M.; Patel, D.V.; Sharr, M.A.; DiJoseph, J.F.; Killar, L.M.; Leone, C.L.; Levin, J.I.; Skotnicki, J.S.; Malonyl alpha-mercaptoketones and alpha-mercaptoalcohols, a new class of matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 1998, 8, 10, 1157. |
| 【2】 Campbell, D.A.; Patel, D.V.; Xiao, X.Y. (Affymax Technologies, NV); Novel inhibitors of collagenase-1 and stromelysin-I metalloproteases, pharmaceutical compsns. comprising same and methods of their use. WO 9640204 . |
| 【3】 Campbell, D.A.; Patel, D.V.; Xiao, X.Y. (Affymax Technologies, NV); Novel inhibitors of metalloproteases, pharmaceutical compsns. comprising same and methods of their use. WO 9640738 . |
| 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) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (II) | 18828 | 1-bromoheptane | 629-04-9 | C7H15Br | 详情 | 详情 |
| (III) | 18829 | methyl 2-acetylnonanoate | C12H22O3 | 详情 | 详情 | |
| (IV) | 18830 | methyl 2-(2-bromoacetyl)nonanoate | C12H21BrO3 | 详情 | 详情 | |
| (V) | 18831 | tritylhydrosulfide; triphenylmethanethiol | 3695-77-0 | C19H16S | 详情 | 详情 |
| (VI) | 18524 | 2-sulfanylacetic acid | 68-11-1 | C2H4O2S | 详情 | 详情 |
| (VII) | 18833 | Trityl alcohol; triphenylmethanol | 76-84-6 | C19H16O | 详情 | 详情 |
| (VIII) | 18834 | 2-(tritylsulfanyl)acetic acid | C21H18O2S | 详情 | 详情 | |
| (IX) | 18835 | N-methoxy-N-methyl-2-(tritylsulfanyl)acetamide | C23H23NO2S | 详情 | 详情 | |
| (X) | 18836 | methyl nonanoate | 1731-84-6 | C10H20O2 | 详情 | 详情 |
| (XI) | 18837 | methyl 2-[2-(tritylsulfanyl)acetyl]nonanoate | C31H36O3S | 详情 | 详情 | |
| (XII) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (XIII) | 18839 | methyl 2-(tritylsulfanyl)acetate | C22H20O2S | 详情 | 详情 | |
| (XIV) | 18840 | 2-(tritylsulfanyl)acetaldehyde | C21H18OS | 详情 | 详情 | |
| (XV) | 18841 | methyl 2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanoate | C31H38O3S | 详情 | 详情 | |
| (XVI) | 18842 | 2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanoic acid | C30H36O3S | 详情 | 详情 | |
| (XVII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (XVIII) | 18844 | N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanamide | C37H50N2O3S | 详情 | 详情 | |
| (XIX) | 18845 | Dess-Martin periodinane; 1,1,1-Triacetoxy-1,2-benziodoxol-3(1H)-one | 87413-09-0 | C13H13IO8 | 详情 | 详情 |
| (XX) | 18846 | N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[2-(tritylsulfanyl)acetyl]nonanamide | C37H48N2O3S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IX)Michael addition of bis(trimethylsilyl)phosphonite (II) to benzyl 2-phenethylacrylate (I) afforded phosphinic acid (III). 4-Benzoylbenzyl bromide (IV) was reduced using triethylsilane and trifluoroacetic acid to give 4-benzylbenzyl bromide (V). Subsequent Arbuzov reaction of phosphinic acid (III) with bromide (V) generated the disubstituted phosphinic acid (VI), which was protected as the methyl ester (VII) employing trimethylsilyl diazomethane. Hydrogenolysis of the benzyl ester of (VII) then yielded carboxylic acid (VIII). This was coupled with (S)-tert-leucinamide (IX) by means of BOP to furnish the corresponding diamide (X). Alternatively, acid (VIII) was treated with N-hydroxysuccinimide (NHS) and EDC, and the resulting succinimidyl ester (XI) was coupled with amine (IX) to produce (X). The methyl phosphinate ester (X) was then deprotected by treatment with aqueous trifluoroacetic acid, and the required (S,S)-diastereoisomer was isolated by reverse phase flash chromatography.
| 【1】 Reiter, L.A.; Rizzi, J.P.; Pandit, J.; et al.; Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket. Bioorg Med Chem Lett 1999, 9, 2, 127. |
| 【2】 Reiter, L.A. (Pfizer Inc.); Phosphinate based inhibitors of matrix metalloproteases. EP 0923585; JP 1999514673; WO 9803516 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 29448 | trimethyl-N-[(Z)-1-(trimethylsilyl)ethylidene]silanamineN-(trimethylsilyl)-N-[(Z)-1-(trimethylsilyl)ethylidene]amine | C8H21NSi2 | 详情 | 详情 | |
| (I) | 29443 | benzyl 2-phenethylacrylate | C18H18O2 | 详情 | 详情 | |
| (II) | 29444 | bis[(trimethylsilyl)methyl]phosphine | C8H23PSi2 | 详情 | 详情 | |
| (III) | 29445 | 2-[(benzyloxy)carbonyl]-4-phenylbutylphosphinic acid | C18H21O4P | 详情 | 详情 | |
| (IV) | 29446 | [4-(bromomethyl)phenyl](phenyl)methanone | C14H11BrO | 详情 | 详情 | |
| (V) | 29447 | 1-benzyl-4-(bromomethyl)benzene | C14H13Br | 详情 | 详情 | |
| (VI) | 29449 | 4-benzylbenzyl[2-[(benzyloxy)carbonyl]-4-phenylbutyl]phosphinic acid | C32H33O4P | 详情 | 详情 | |
| (VII) | 29450 | benzyl 2-[[(4-benzylbenzyl)(methoxy)phosphoryl]methyl]-4-phenylbutanoate | C33H35O4P | 详情 | 详情 | |
| (VIII) | 29451 | 2-[[(4-benzylbenzyl)(methoxy)phosphoryl]methyl]-4-phenylbutyric acid | C26H29O4P | 详情 | 详情 | |
| (IX) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (X) | 29452 | methyl 4-benzylbenzyl[2-[([(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]amino)carbonyl]-4-phenylbutyl]phosphinate | C33H43N2O4P | 详情 | 详情 | |
| (XI) | 29453 | methyl 4-benzylbenzyl(2-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-4-phenylbutyl)phosphinate | C30H32NO6P | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(X)Allyl ester (IV) is subjected to Claisen-Ireland rearrangement in the presence of strong bases to produce a diastereomeric mixture of pentenoic acids, from which the desired isomer (IX) can be isolated via crystallization of its (S)-phenylethylamine salt. Subsequent coupling of acid (IX) with tert-leucine methylamide (X) provides amide (XI). Oxidative cleavage of the terminal olefin of (XI) to aldehyde (XII) is performed by either treatment with NaIO4 or by ozonolysis. Aldehyde (XII) is further oxidized to the carboxylic acid (XIII) employing NaClO2. Coupling of acid (XIII) with O-benzyl hydroxylamine yields the benzyl-protected hydroxamate (XIV). The title compound is finally obtained by hydrogenolysis of the benzyl groups of (XIV) in the presence of Pd/BaSO4.
| 【1】 Koch, G.; Kottirsch, G.; Wietfeld, B.; Kusters, E.; Process development of a dual MMP/TNF inhibitor (SDZ 242-484). Org Process Res Dev 2002, 6, 5, 652. |
| 【2】 Kottirsch, G.; et al.; beta-Aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme. J Med Chem 2002, 45, 11, 2289. |
| 【3】 Kottirsch, G.; Neumann, U. (Novartis AG); Hydroxamic acid derivs.. EP 0929517; JP 2000508338; US 2002003804; US 6500983; WO 9814424 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 61681 | (E)-4-(benzyloxy)-2-butenyl 2-(4-methoxyphenyl)acetate | C20H22O4 | 详情 | 详情 | |
| (IX) | 61684 | (2S,3R)-3-[(benzyloxy)methyl]-2-(4-methoxyphenyl)-4-pentenoic acid | C20H22O4 | 详情 | 详情 | |
| (X) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (XI) | 61685 | (2S,3R)-3-[(benzyloxy)methyl]-N-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-2-(4-methoxyphenyl)-4-pentenamide | C27H36N2O4 | 详情 | 详情 | |
| (XII) | 61686 | (2S)-2-{[(2S,3R)-4-(benzyloxy)-3-formyl-2-(4-methoxyphenyl)butanoyl]amino}-N,3,3-trimethylbutanamide | C26H34N2O5 | 详情 | 详情 | |
| (XIII) | 61687 | (2R,3S)-2-[(benzyloxy)methyl]-4-({(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}amino)-3-(4-methoxyphenyl)-4-oxobutanoic acid | C26H34N2O6 | 详情 | 详情 | |
| (XIV) | 61688 | (2R,3S)-N~1~-(benzyloxy)-2-[(benzyloxy)methyl]-N~4~-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-3-(4-methoxyphenyl)butanediamide | C33H41N3O6 | 详情 | 详情 |