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【结 构 式】 
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【分子编号】25390 【品名】4-methylpentanoyl chloride 【CA登记号】38136-29-7 |
【 分 子 式 】C6H11ClO 【 分 子 量 】134.60544 【元素组成】C 53.54% H 8.24% Cl 26.34% O 11.89% |
合成路线1
该中间体在本合成路线中的序号：(II)1) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with benzyl bromoacetate (V) by means of LDA in THF affords the (S)-adduct (VI) with >95% e.e. purity. The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (VII), which is reduced with BH3/SMe2 in THF, yielding compound (VIII). The reaction of (VIII) with tosyl chloride in pyridine yields the tosylate (IX), which is treated with sodium azide in DMSO, affording the azide (X). Finally, this compound is reduced and debenzylated with H2 over Pd/C in THF.
| 【1】 Bryans, J.S.; Wustrow, D.J.; 3-Substituted GABA analogs with central nervous system activity: A review. Med Res Rev 1999, 19, 2, 149. |
| 【2】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348. |
| 【3】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26. |
| 【4】 Taylor, C.P.; Kanter, G.D.; Vartanian, M.G.; Yuen, P.; Enantioselective synthesis of PD144723: A potent stereospecific anticonvulsant. Bioorg Med Chem Lett 1994, 4, 6, 823. |
| 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) | 25389 | 4-methylpentanoic acid | 646-07-1 | C6H12O2 | 详情 | 详情 |
| (II) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (III) | 26040 | (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C10H11NO2 | 详情 | 详情 | |
| (IV) | 26041 | (4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (V) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 26042 | benzyl (3S)-5-methyl-3-[[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl]hexanoate | C25H29NO5 | 详情 | 详情 | |
| (VII) | 26043 | (2S)-2-[2-(benzyloxy)-2-oxoethyl]-4-methylpentanoic acid | C15H20O4 | 详情 | 详情 | |
| (VIII) | 26044 | benzyl (3S)-3-(hydroxymethyl)-5-methylhexanoate | C15H22O3 | 详情 | 详情 | |
| (IX) | 26045 | benzyl (3S)-5-methyl-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)hexanoate | C22H28O5S | 详情 | 详情 | |
| (X) | 26046 | benzyl (3S)-3-(azidomethyl)-5-methylhexanoate | C15H21N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)2) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with tert-butyl bromoacetate (XI) by means of LDA in THF affords the (S)-adduct (XII). The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (XIII), which is reduced with BH3/SMe2 in THF, yielding compound (XIV). The reaction of (XIV) with tosyl chloride in pyridine yields the tosylate (XV), which is treated with sodium azide in DMSO, affording the azide (XVI). The hydrolysis of the tert-butyl group of (XVI) affords the free acid (XVII), which is reduced with H2 over Pd/C.
| 【1】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348. |
| 【2】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26. |
| 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) | 25389 | 4-methylpentanoic acid | 646-07-1 | C6H12O2 | 详情 | 详情 |
| (II) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (III) | 26040 | (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C10H11NO2 | 详情 | 详情 | |
| (IV) | 26041 | (4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (XI) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XII) | 26047 | tert-butyl (3S)-5-methyl-3-[[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl]hexanoate | C22H31NO5 | 详情 | 详情 | |
| (XIII) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (XIV) | 26048 | tert-butyl (3S)-3-(hydroxymethyl)-5-methylhexanoate | C12H24O3 | 详情 | 详情 | |
| (XV) | 26049 | tert-butyl (3S)-5-methyl-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)hexanoate | C19H30O5S | 详情 | 详情 | |
| (XVI) | 26050 | tert-butyl (3S)-3-(azidomethyl)-5-methylhexanoate | C12H23N3O2 | 详情 | 详情 | |
| (XVII) | 26051 | (3S)-3-(azidomethyl)-5-methylhexanoic acid | C8H15N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)4-Methylvaleric acid (I) was converted to acid chloride (II) and then condensed with (S)-4-benzyl-2-oxazolidinone (III) to give (IV). Subsequent alkylation of (IV) with tert-butyl bromoacetate (V) in the presence of sodium bis(trimethylsilyl)amide produced the chiral intermediate (VI), which was hydrolyzed with lithium peroxide to yield (R)-2-isobutylsuccinic acid 4-tert-butyl ester (VII). Further alkylation of (VII) with 4-bromo-1-butene (VIII) afforded a 6:1 mixture of syn/anti isobutenyl compounds (IX), which upon isomerization with LDA in THF at -20 C, followed by quenching with MeOH, provided a 1:1.5 mixture of isomers. Condensation of N-Boc-L-tyrosine (X) with methylamine in the presence of EDC and HOBt gave amide (XI). Then, removal of the Boc protecting group with HCl in dioxan yielded tyrosinamide (XII). This was coupled to succinic acid derivative (IX) using EDC and HOBt to afford the corresponding amide (XIII) as an epimeric mixture. Hydroboration of the butenyl double bond, followed by oxidative treatment with H2O2 produced alcohol (XIV).
| 【1】 Sheppard, G.S.; Guo, Y.; Siummers, J.B.; Holms, J.H.; Steinman, D.H.; Michaelides, M.R.; Florjancic, A.S.; Xu, L.; Davidsen, S.K. (Abbott Laboratories Inc.); Macrocyclic inhibitors of matrix metalloproteinases and TNFalpha secretion. EP 1021423; WO 9830551 . |
| 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) | 25389 | 4-methylpentanoic acid | 646-07-1 | C6H12O2 | 详情 | 详情 |
| (II) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (III) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (IV) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 25392 | tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate | C22H31NO5 | 详情 | 详情 | |
| (VII) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (VIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (IX) | 25394 | (2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-heptenoic acid | C16H28O4 | 详情 | 详情 | |
| (X) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (XI) | 25396 | tert-butyl (1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethylcarbamate | C15H22N2O4 | 详情 | 详情 | |
| (XII) | 25397 | (2S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide | C10H14N2O2 | 详情 | 详情 | |
| (XIII) | 25398 | tert-butyl 2-[(1R)-1-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-5-hexenoate | C26H40N2O5 | 详情 | 详情 | |
| (XIV) | 25399 | tert-butyl (3R)-3-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-2-(4-hydroxybutyl)-5-methylhexanoate | C26H42N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).
| 【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 . |
| 【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 | |
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (II) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (III) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (IV) | 25392 | tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate | C22H31NO5 | 详情 | 详情 | |
| (V) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (VI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VII) | 35082 | (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid | C15H26O4 | 详情 | 详情 | |
| (VIII) | 35083 | (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid | C15H26O4 | 详情 | 详情 | |
| (IX) | 35084 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C22H32O4 | 详情 | 详情 | |
| (X) | 35085 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate | C22H34O5 | 详情 | 详情 | |
| (XI) | 35086 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate | C29H37NO9 | 详情 | 详情 | |
| (XII) | 35087 | methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate | C15H22N2O4 | 详情 | 详情 | |
| (XIII) | 35088 | 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate | C38H54N2O10 | 详情 | 详情 |